This Article Extract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Schaper, W. Articles by Ito, W. D. Search for Related Content PubMed PubMed Citation Articles by Schaper, W. Articles by Ito, W. D.

(Circulation Research. 1996;79:911-919.)
© 1996 American Heart Association, Inc.

Articles

Molecular Mechanisms of Coronary Collateral Vessel Growth

Wolfgang Schaper, Wulf D. Ito

the Max-Planck-Institute for Physiological and Clinical Research, Department of Experimental Cardiology, Bad Nauheim, Germany.

Correspondence to Prof Dr Wolfgang Schaper, Max-Planck-Institute for Physiological and Clinical Research, Department of Experimental Cardiology, Benekestrasse 2, D-61231 Bad Nauheim, Germany.

Key Words: angiogenesis • collateral arteries • heart

	Introduction

Top Introduction Collaterals Develop by Mitotic... Growth Factors, Their Receptors,... Inhibitors of Vascular Growth Role of Hypoxia Angiogenesis and Vasculogenesis Remodeling of Epicardial... Influence of Shear Stress Quantification of Collateral... Therapeutic Angiogenesis Limits of Collateral Growth Summary and Conclusions References

 
Growth of coronary collaterals can change markedly the natural history of coronary artery disease: Stenoses and occlusions of the coronary arteries, even of the left main coronary artery, can be survived without infarction provided that the stenosing process has not progressed too fast, since the process of collateral development by growth needs time (a few weeks).^{1 2 3}

However, in most cases, thrombus formation proceeds faster than vascular growth and infarcts develop. In many cases, collaterals, although they cannot prevent infarction in the majority of cases, may limit the damage and infarcts are smaller than expected from the size of the region at risk.⁴

Understanding collateral growth may mean to be potentially and eventually able to stimulate it by the injection of drugs, by the injection of growth factors, or by somatic gene therapy in patients at risk of infarction.

	Collaterals Develop by Mitotic Growth

Top Introduction Collaterals Develop by Mitotic... Growth Factors, Their Receptors,... Inhibitors of Vascular Growth Role of Hypoxia Angiogenesis and Vasculogenesis Remodeling of Epicardial... Influence of Shear Stress Quantification of Collateral... Therapeutic Angiogenesis Limits of Collateral Growth Summary and Conclusions References

 
In the past we have shown that collaterals grow by DNA synthesis and mitosis of endothelial and smooth muscle cells.³ These cells are quiescent in normal adult arteries, with their population kinetics close to zero. Under abnormal conditions a rapid conversion to G₁ can occur and the cell cycle can be completed in 22 hours.³

With rapidly progressing stenosis in dogs (3 days from the onset of stenosis to complete occlusion), the labeling index of the endothelium of the midzone segment reached 7.5% and was followed by a wave of smooth muscle cell mitosis of only slightly lesser magnitude.

Since controlled and regulated growth does not proceed without the presence and action of growth factor peptides and their receptors, several groups have investigated that aspect.^{5 6 7 8}

	Growth Factors, Their Receptors, and Their Inhibitors

Top Introduction Collaterals Develop by Mitotic... Growth Factors, Their Receptors,... Inhibitors of Vascular Growth Role of Hypoxia Angiogenesis and Vasculogenesis Remodeling of Epicardial... Influence of Shear Stress Quantification of Collateral... Therapeutic Angiogenesis Limits of Collateral Growth Summary and Conclusions References

 
The growth factors that are potentially involved in the process of cardiac collateralization are aFGF, bFGF, VEGF, IGF-1, and PDGF.^{7 9 10 11 12 13} With the exception of PDGF and bFGF, these growth factors are constitutively expressed in normal porcine myocardium and can be demonstrated by Northern hybridization.⁵ The proteins can be determined by Western blot or other protein-biochemical methods but not by indirect immunofluorescence, probably because their concentrations are below the threshold of detection of this method.⁵ The localization of these proteins in myocardial tissue is therefore unknown. Indirect evidence points toward the extracellular matrix, since all of these growth factors bind to heparin.⁷

The presence of receptors for these factors in the adult normal heart has been thus far also only indirectly inferred from binding studies of radioactively labeled VEGF¹⁴ and directly for the FLT1 receptor of VEGF,¹⁵ which is not responsible for its mitogenic response.¹⁶ Another single binding site has been found on monocytes.¹⁷ Since VEGF is a chemoattractant for monocytes,¹⁸ chemoattraction could be the role conveyed by this binding site, which was shown in a recent paper by Barleon et al.¹⁹ In fact the chemoattractive effect of VEGF may be more important for angiogenesis than its weak mitogenic effect. However, it is highly likely that collaterals develop only when growth or angiogenic factors are present and their receptors expressed. Little in terms of formal proof exists that this is so under in vivo conditions in the collateralized heart. According to our present knowledge, no studies exist that show by in situ hybridization upregulation of the mRNA for the major growth factors and their receptors in close proximity to growing vessels except IGF-1 and aFGF in microembolized porcine myocardium.^{20 21}

Although monocytes/macrophages are known to produce a host of angiogenic growth factors when adequately stimulated,^{18 22 23 24 25} no in-vivo data are available to substantiate this except those of TNF- (an indirectly acting angiogenic factor), which we have demonstrated by indirect immunofluorescence on epicardial canine collaterals.⁵

VEGF is a weak mitogen compared with certain other mitogens like aFGF, which we have found also to be upregulated during collateral development in the heart.^{7 21} Goto et al²⁶ were able to show that the mitogenic response is potentiated when VEGF and FGF are given together in cell cultures. This may be due to a reciprocal upregulation of receptors.

Several growth factor mRNAs are upregulated in the porcine microembolized heart and it is difficult to know how their proteins interact. By using the first appearance of endothelial cell mitoses after microembolization as a reference point, we found that VEGF appears and fades probably too soon (30 minutes after occlusion), that aFGF appears too late (1 to 3 days after mitosis, with a peak at 7 days), and that IGF-1 appears at the right time (12 hours before mitosis).^{5 20} Except for aFGF, all attempts to study growth factor proteins have thus far failed because of the insensitivity of the available methods or because of insufficient cross-reactivity with the pig antigen.

It is of interest to note from the literature of tumor angiogenesis that the upregulation of the receptor number is an important regulatory mechanism.^{27 28} The previously prevailing view was that the supply of the growth factor was the only important event to start angiogenesis. We (and probably many other groups that also did not publish their negative results) learned that the infusion of growth factors into normal hearts did not result in angiogenesis, probably because of the absence of receptors in normal tissue. The events that lead to upregulation of receptors are not well understood, but factors involved in inflammation (ie, cytokines) may play a role. It also has been shown that the FLK and FLT receptors are upregulated by hypoxia in the lung,²⁹ and Plate et al³⁰ showed that upregulation of the VEGF receptor is a first step in brain tumor angiogenesis. Unphysiological conditions such as when endothelium is put into culture may also contribute to the upregulation of receptors. Cultured endothelium but not in vivo endothelium exhibits abundant receptors for FGF and VEGF.¹⁶

	Inhibitors of Vascular Growth

Top Introduction Collaterals Develop by Mitotic... Growth Factors, Their Receptors,... Inhibitors of Vascular Growth Role of Hypoxia Angiogenesis and Vasculogenesis Remodeling of Epicardial... Influence of Shear Stress Quantification of Collateral... Therapeutic Angiogenesis Limits of Collateral Growth Summary and Conclusions References

 
An unexplained observation is the presence of specific binding sites for VEGF in the normal heart in the presence of the ligand but in the absence of any significant proliferation.¹⁵ It was this observation that stimulated us to search for a natural inhibitor of angiogenesis that interferes with the binding of the ligand with its growth factor receptor. We found in normal bovine heart such an inhibitor of cell proliferation, which acts competitively, ie, its effects can be reversed by increasing the agonist concentration.³¹ We recently cloned a gene that shows partial homology with the antiproliferative gene BTG1 (B-cell translocation gene),³² previously isolated from a leukemic cell line. Other inhibitors of angiogenesis have been described in the context of placental growth or tumor angiogenesis. These include platelet factor 4, thrombospondin-1, tissue inhibitors of metalloproteinases, prolactin, angiostatin, bFGF soluble receptor, TGF-ß, interferon , and placental proliferin-related protein.^{33 34 35 36} However, except for TGF-ß,⁵ which is also an angiogenesis inducer by virtue of its chemotactic effect on monocytes, none of these have been shown to play a role in ischemia-related angiogenesis in the heart, and TGF-ß has not been tested in vivo as an inhibitor of angiogenesis.

Vascular growth may therefore require three elements of control: agonist supply, upregulation of the receptor, and inhibition of the inhibitor. Absence of cell proliferation in the presence of growth factors in the normal heart may also mean that these factors have other or additional physiological functions, ie, as trophic factors.

	Role of Hypoxia

Top Introduction Collaterals Develop by Mitotic... Growth Factors, Their Receptors,... Inhibitors of Vascular Growth Role of Hypoxia Angiogenesis and Vasculogenesis Remodeling of Epicardial... Influence of Shear Stress Quantification of Collateral... Therapeutic Angiogenesis Limits of Collateral Growth Summary and Conclusions References

 
It is known that acute tissue ischemia rapidly upregulates VEGF mRNA. A 10-minute coronary occlusion followed by reperfusion leads to a threefold increase in the cardiac VEGF mRNA concentration.⁹ It is unknown whether the fast upregulation of VEGF after brief ischemia is related to the angiogenic response^{37 38 39 40 41 42} because short coronary occlusions/reperfusions have to be repeated hundreds of times before an angiogenic response can be detected.⁴³

The mechanism of VEGF upregulation by hypoxia has been unraveled recently: Like other hypoxia-inducible genes (ie, induced with erythropoietin, LDH, and FGF), VEGF has a hypoxia recognition site (hypoxia inducible factor) in its promoter sequence.⁴⁴ In addition, VEGF mRNA stability can vary. Adenosine (via the A₁ receptor) increases VEGF stability.⁴⁵

Adenosine formation stems from the ischemia-induced catabolism of high-energy phosphates.⁴⁶ Ikeda et al⁴⁴ investigated the influence of hypoxia on the transcriptional activation and increased VEGF mRNA stability observed in glioma cells. They were able to show that there is a fast induction of transcriptional activation of VEGF mRNA during hypoxia and a slower increase of VEGF mRNA stability.^{9 39 40 44} The double-barrel regulation of VEGF expression by increased transcription and increased stability points to an important role of that molecule in hypoxia-related angiogenesis. Recapitulated vasculogenesis (see below) may, however, need mechanisms that differ from tissue hypoxia, and effects of VEGF, if present at all, may be indirect.

However strong the association of ischemia with collateral vasculogenesis may be, its correlation is probably only spurious. Collateral growth in the canine model occurs in the epicardium where no hypoxia is present and proceeds at a time when even the endocardium is not hypoxic anymore.⁵ Fulton¹ had already shown that the enlarged "stem" of epicardial collaterals can lie outside the perfusion area (risk region) of the occluded artery. It is because of this spatial and temporal dissociation of the presumed stimulus and the response that we doubt the role that hypoxia is believed to play.

Another drastic example of a mismatch between the site of ischemia and the site of collateral growth can be found in the peripheral circulation: The foot is ischemic but collaterals develop in the thigh region in femoral artery occlusion.⁴⁷ We therefore believe that collateral growth is a local phenomenon restricted to the relatively short segment of vessel undergoing remodeling, and that local forces (ie, stresses and inflammation) play the dominant role. Growth factors are probably produced by invading monocytes,⁴⁸ and cytokines may be involved in the upregulation of receptors.

In the pig heart (where angiogenesis indeed occurs in ischemic myocardium) angiogenesis is mainly observed around microinfarcts. We believe that it is, here again, the inflammatory milieu that stimulates angiogenesis.^{5 22 49}

	Angiogenesis and Vasculogenesis

Top Introduction Collaterals Develop by Mitotic... Growth Factors, Their Receptors,... Inhibitors of Vascular Growth Role of Hypoxia Angiogenesis and Vasculogenesis Remodeling of Epicardial... Influence of Shear Stress Quantification of Collateral... Therapeutic Angiogenesis Limits of Collateral Growth Summary and Conclusions References

 
Vascular growth is usually categorized into angiogenesis, (ie, the sprouting of new capillaries from preexisting ones) and vasculogenesis (the in situ development of vessels from angioblasts that is normally confined to the embryonic phase of development and results mainly in the formation of the large arteries).⁵⁰ The vascular system of organs like kidney and brain develops via angiogenic pathways.⁵¹

Collateral formation can proceed via either pathway: Epicardial collaterals develop by enlargement of preexisting arterioles into muscular arteries "in situ," they recapitulate vasculogenesis; whereas small subendocardial collaterals develop de novo and they recapitulate angiogenesis. True angiogenesis (ie, capillary sprouting and increased capillary density) occurs in the porcine heart with chronic ameroid-induced coronary occlusion, and it significantly reduces the minimal vascular resistance of the entire collateral-dependent region.^{52 53 54 55 56} This response is preceded by increased expression of urokinase-type plasminogen activator and later by expression of PAI-1.⁵

Numerous small collaterals that develop de novo are typical for the porcine model (ameroid and microembolization) of collateral vessel growth, and they are also the more frequent response in the human heart. They often look like enlarged capillaries and lack a smooth muscular coat.⁵⁷ These small porcine collaterals usually develop near focal necroses.

The production of focal necroses by microembolization with 15-µm plastic beads leads also to an angiogenic response similar to that caused by ameroid constriction of large arteries. An angiogenesis model based on microembolization was developed by Chilian et al⁵⁸ who found that it increased collateral flow in the canine heart. We adopted and modified this model because of its technical simplicity.⁵

Angiogenesis responds favorably to physical exercise, as numerous studies by Bloor's group have shown.^{59 60 61 62} Recapitulated vasculogenesis (growth of epicardial muscular collaterals) does not.⁶³

Collateral vasculogenesis consists of two phases, ie, proliferation and remodeling. Proliferation starts with the endothelium that exhibits an early steep rise in the labeling index during fast progressive coronary occlusion (3 days from onset to occlusion), followed by smooth muscle cell mitosis (Fig 1).^{23 64} The new smooth muscle is all intimal and exhibits a longitudinal and helical orientation (Fig 2). It consists of dedifferentiated smooth muscle cells that have lost most of the adult ultrastructural characteristics, including loss of most of the actin filaments. It represents the "synthesis type" of smooth muscle cells in contrast to the physiological contractile type.³ The synthesis type produces extracellular matrix, collagen, and elastin and will finally produce a new internal elastic lamina.⁵

View larger version (293K): [in this window] [in a new window]   Figure 1. A normal (left) and an "activated" endothelial cell from an early stage of collateral remodeling. Both micrographs were taken at identical magnifications. The activated endothelial cell is much larger and it exhibits the "synthesis" type with increased amounts of endoplasmic reticulum and mitochondria. Monocytes adhere at this stage.

View larger version (150K): [in this window] [in a new window]   Figure 2. An endothelial and a smooth muscle cell mitosis (arrows) in a rapidly forming intima in an epicardial canine collateral vessel about 1 week after closure of a progrediently stenosing LCX.

	Remodeling of Epicardial Preexistent Collaterals

Top Introduction Collaterals Develop by Mitotic... Growth Factors, Their Receptors,... Inhibitors of Vascular Growth Role of Hypoxia Angiogenesis and Vasculogenesis Remodeling of Epicardial... Influence of Shear Stress Quantification of Collateral... Therapeutic Angiogenesis Limits of Collateral Growth Summary and Conclusions References

 
The term "remodeling" is used in atherosclerosis and restenosis research to emphasize that processes are active to maintain normal vessel dimensions in the presence of stenosing influences. Collateral vasculogenesis is probably the most drastic example of remodeling, with its increase of up to 20-fold of the initial diameter and increase in tissue mass of up to 50-fold. Although collateral growth has many features in common with other vascular alterations (monocyte adhesion and intima formation as in atherosclerosis), its degree of remodeling makes it unique (Fig 3). Remodeling provides the space for the new tissue mass and it consists of controlled destruction of the old much smaller vessel and it also involves adventitial restructuring by controlled cardiac myocyte death to accommodate the greatly enlarged vessel in its tissue bed. Remodeling starts with the dissolution or weakening of the smooth muscle cell-to-cell adhesion (extracellular matrix) that results in structural dilatation of the small arteriole that becomes leaky with extravasation of proteins, notably fibrinogen, and becomes invaded by monocytes and lymphocytes.⁵ Leakiness may be the result of VEGF expression⁶⁵ and may aid in the formation of a new extracellular matrix.

View larger version (93K): [in this window] [in a new window]   Figure 3. Electron micrograph of a canine epicardial collateral artery about 3 weeks after progredient closure of the LCX. The lumen is on the upper left-hand side. The intima is highly disorganized and consists of migrating and proliferating smooth muscle cells of the "synthesis" type that produce large amounts of extracellular matrix. There is evidence of apoptotic cell death from the phagocytosis of remnants of smooth muscle cells by smooth muscle cells (see arrow). In later stages the size of the intimal hyperplasia regresses, the new smooth muscle assumes its normal orientation and an almost normal appearance results.

Simultaneously, the internal elastic membrane ruptures after proteolysis by elastase, and programmed cell death of a significant proportion of the "old" circular smooth muscle cells occurs. It can be envisaged that the TNF-–producing monocytes are also instrumental in apoptosis that can be triggered via TNF- receptors.^{3 66 67}

The onset of matrix lysis by expression of proteases may be triggered by the same factors that initiate mitosis. Pepper and others have described an interesting counterregulatory mechanism by which urokinase-type plasminogen activator and to a lesser extent its inhibitor PAI-1 are upregulated by bFGF and VFGF, whereas the angiogenesis inhibitor TGF-ß mainly upregulates PAI-1.^{8 68 69 70 71 72 73 74 75}

Intimal proliferation of smooth muscle cells can overshoot and the new collateral lumen becomes actually smaller or obliterates completely⁴ (Fig 4). This may have to do with competition for blood flow.^{76 77} Provided that growth of collateral vessels is dependent upon blood flow velocity, initially larger vessels have a growth advantage. As they enlarge, they conduct an increasingly larger proportion of the total flow, which reduces the shear stress forces in the smaller vessels. Reduction of shear stress forces within smaller vessels that are already mitotically stimulated reduces the remodeling influence and leads to overshooting intimal proliferation and increased fibronectin expression^{5 78} (Fig 5). The regression of smaller collaterals in favor of a few larger ones due to shear stress was also demonstrated recently in a mathematical model by Hacking et al.⁷⁹ Overshooting intimal proliferation and increased fibronectin expression may be caused by increased PDGF production.⁷⁷ This view is supported by similar findings of the Clowes group in prosthetic artery experiments,⁸⁰ but it clashes with several in vitro studies^{81 82 83 84} in which increased fluid shear stress upregulates PDGF expression. It can also be envisaged that overshooting intimal hyperplasia (which is useful because it reduces the initially large number of responding small collaterals in favor of a few large ones that are better bulk flow conductors) is caused by a failure of smooth muscle cell apoptosis and/or by a failure of matrix protease expression. Increased expression of fibronectin is a recourse to embryonic patterns of vascular gene expression.^{45 51}

View larger version (161K): [in this window] [in a new window]   Figure 4. Failure of a collateral vessel to remodel. The intimal proliferation had reduced the lumen, and the old lamina media is still present and is not destroyed as in successful cases of collateral remodeling.

View larger version (156K): [in this window] [in a new window]   Figure 5. Increased extracellular matrix formation in an epicardial canine collateral vessel with failed remodeling. There is an overabundance of fibronectin (green stain). The lumen is almost completely obliterated.

	Influence of Shear Stress

Top Introduction Collaterals Develop by Mitotic... Growth Factors, Their Receptors,... Inhibitors of Vascular Growth Role of Hypoxia Angiogenesis and Vasculogenesis Remodeling of Epicardial... Influence of Shear Stress Quantification of Collateral... Therapeutic Angiogenesis Limits of Collateral Growth Summary and Conclusions References

 
Thoma's "Law of Histiomechanics," published in 1893,⁸⁵ still holds true. It says that there is a relationship between the size of an artery and the velocity of blood flow within it. This relationship is not merely descriptive but probably also the expression of a molding force: Large vessels with a low flow (ie, bypass vessels with a low runoff) tend to close or to reduce their lumen, whereas small vessels with a chronically increased high flow tend to get wider (via remodeling or collateral development).⁸⁶

Fluid shear stress forces may act as molding forces in the development of epicardial collaterals that preexist as small arteriolar structures. According to one possible scenario, increased fluid shear stress forces in connecting arterioles caused by the pressure difference due to large vessel stenosis lead to upregulation of adhesion molecules in the endothelium,^{87 88} attract monocytes that become activated (produce TNF- and VEGF, attract more monocytes, produce growth factors,^{17 18 48} ), and stimulate endothelium to produce bFGF and PDGF, which (together with those produced by monocytes) lead to endothelial and smooth muscle cell mitoses.⁸⁹ In addition, shear stress itself seems to stimulate directly the production of certain growth factors (ie, PDGF, bFGF, TGF-ß) in endothelial cells.^{90 91} A shear stress–responsive enhancer element has been described for PDGF and aFGF. Tissue plasminogen activator, which may have a role in remodeling, is also upregulated by shear stress.⁹⁰

Although several of the individual steps in this hypothesis are observed fact, others are contradictory. TNF- has an antimitogenic effect on endothelium, and increased shear stress increases the expression of inducible NO synthase and leads to increased production of NO,⁹² which downregulates the expression of VEGF and its receptors^{29 93} as well as that of the monocyte chemoattractant protein-1⁹⁴ (Fig 6). It appears difficult to reconcile these opposing forces and we postulate that chronically increased shear stress forces that act over days may produce a pattern that differs from that of short-term experiments from which results cited above were obtained. We found signs of endothelial activation (increased endoplasmic reticulum), damaged endothelium, endothelial denudation, and platelet adhesion in canine epicardial collaterals.⁹⁵

View larger version (57K): [in this window] [in a new window]   Figure 6. A flowchart explaining the partially hypothetical cellular and molecular events that lead to large-caliber collateral vessel formation on the subepicardial surface (left) and to numerous small collaterals that develop de novo throughout the entire left ventricular wall in the porcine model (right).

	Quantification of Collateral Resistance

Top Introduction Collaterals Develop by Mitotic... Growth Factors, Their Receptors,... Inhibitors of Vascular Growth Role of Hypoxia Angiogenesis and Vasculogenesis Remodeling of Epicardial... Influence of Shear Stress Quantification of Collateral... Therapeutic Angiogenesis Limits of Collateral Growth Summary and Conclusions References

 
In order to quantitate collateral growth, collateral resistances have to be determined. Analogous to electrical circuits, this requires the measurement of the pressure gradient across collaterals relative to the flow through them. Since collaterals are in series with the resistance of the distal circulation, collateral flow is identical to the flow through the receiving bed. For the measurement of the pressure gradient, the source pressure (not significantly different from aortic pressure) must be determined from which the peripheral coronary pressure (the pressure in the distal stump of the occluded artery) is subtracted. Dividing the pressure difference (aortic pressure minus peripheral coronary pressure) by the collateral flow provides collateral resistance. Dividing peripheral coronary pressure by distal flow equals the minimal resistance of the receiving bed circulation provided that a "resistance clamping" at maximal vasodilation was established. In the dog, mature collateral vessels 2 to 3 months after onset of a progredient stenosis exhibit a resistance that equals that of the entire dependent resistance downstream from the in-series collaterals.⁹⁶ In comparison with the resistance of the artery that was replaced by collaterals, collateral resistance proper is much higher and total resistance of the collateral dependent region is at least 2 times higher than that of a normal region. This means that the dilatory reserve had shrunk from 5 times normal flow to 2 to 3 times normal flow. This may give rise to unequal flow distribution under increased demand, showing that there is still a wide margin for improvement by therapy.

In contrast to resistances in electrical circuits, vascular resistances depend upon the material properties of the vessel wall and on blood viscosity. This contributes to the phenomenon of a positive-pressure intercept at zero flow, which is dependent on the degree of vasodilation. Therefore, resistances should be calculated only from the slope of the plot: pressure versus flow except when the zero-flow pressure intercept is known.

In the case of many small collaterals as in the porcine heart, the calculation of collateral resistance is more complicated because not only had the collateral resistance proper changed but also the minimal resistance of the dependent microcirculation. In general the degree of adaptation by small collaterals in the porcine model is much less than that by epicardial collaterals in the canine model.

	Therapeutic Angiogenesis

Top Introduction Collaterals Develop by Mitotic... Growth Factors, Their Receptors,... Inhibitors of Vascular Growth Role of Hypoxia Angiogenesis and Vasculogenesis Remodeling of Epicardial... Influence of Shear Stress Quantification of Collateral... Therapeutic Angiogenesis Limits of Collateral Growth Summary and Conclusions References

 
Recently, therapeutic angiogenesis was attempted in animal models. In several studies, growth factor peptides were either infused directly into the coronary circulation or were infused or injected intravenously, were applied by osmotic minipump by "close arterial" infusion, or were coupled to microsphere beads. In other studies, transfer of growth factor genes was attempted.^{97 98 99 100 101 102 103 104 105 106}

Most of these studies showed an increase of collateral blood flow or at least an interesting tendency toward preservation of ventricular function under strain. Many questions remain unsolved, among which are the range of peptide concentrations necessary for a measurable effect and the precise timing of administration during the process of collateralization.

In one study,¹⁰⁶ the bFGF peptide was injected into anesthetized dogs 1 hour after acute coronary artery occlusion, and ejection fraction, infarct size, and capillary density were determined days later. All these parameters showed improvement in the treatment group, which is in contrast to traditional views given the late injection of the growth factor, the quick death of ischemic myocardium, and the long time requirements of the mitotic response of endothelial and smooth muscle cells (22 hours).

Another interesting report showed that the adventitial deposition of encapsulated bFGF to the proximal part of the LCX and LAD regions "improves myocardial function in chronically ischemic porcine hearts."¹⁰³ Collateral resistance was improved by bFGF, but arterial pressure fell more during pacing in the bFGF group. Infarct size (ratio of infarct region to left ventricular mass) was significantly reduced in bFGF-treated pigs, but left ventricular mass increased more in the treated group and hence influenced the ratio.

The method of bFGF administration by adventitial deposition of a slow-release bFGF preparation is unorthodox in that the depot and the locale of angiogenesis are so far apart.

In a paper by Baird's group,⁹⁸ bFGF was also deposited as a depot near the rat carotid adventitia, and a mitotic response of the vasa vasorum was obtained. The effect was strictly local and no cell proliferation was observed even at 2 mm from the infusion site.

Infusion of bFGF into the peripheral arterial stump of the ameroid-occluded canine LCX was studied by Unger and coworkers.¹⁰⁵ This place of injection bypasses the developing collaterals in the first passage. Only recirculating bFGF reaches the epicardial collaterals that interconnect the LAD and the right coronary artery with the LCX. Therefore, in a subsequent study the authors used intravenous injection instead.¹⁰⁷

The end point of the study was to improve collateral blood flow, which was measured as the ratio of microsphere content of ischemic versus normal regions during maximal vasodilation. Although this gives an adequate impression of the degree of compensation by collaterals, true collateral resistance could not be determined.

Unger et al concluded from their studies that bFGF exerted its most convincing action at the time of presumed closure of the ameroid, ie, at the time of tissue ischemia. This may be so and reflects the tendency of the FGF receptors to downregulate under physiological conditions. A pathological stimulus is required to upregulate them again. This view is not shared by Baird's group who have stated that the bioavailability of the growth factor is of exclusive importance.¹⁰⁸

VEGF was also tried by Unger's group in the same dog model⁹⁷ (injection into the peripheral stump of the occluded LAD), and results similar to those with bFGF were obtained: Significantly higher microsphere counts in the collateral dependent bed at days 24 and 38 but not at day 31. Although VEGF is a specific (but not very potent) mitogen for endothelial cells, capillary density remained unchanged, but the number of muscular distribution vessels increased (somewhat unexpectedly) in the collateral dependent region. The authors speculate that VEGF-activated endothelium might have produced PDGF. In another study, Unger's group produced a balloon-injury lesion in the femoral artery together with the ameroid implantation in the heart and injected VEGF intravenously daily¹⁰⁹ (personal communication, M. Scheinowitz, 1996). The mild stimulating effect on coronary collaterals was offset by the observation that the balloon-injury lesion in the femoral artery became worse.

Although 2 weeks of daily injections of high VEGF concentrations were needed to achieve a relatively modest effect in Unger's canine model, Isner's group¹⁰⁴ showed that a single intra-arterial dose of VEGF had a beneficial effect on hind-limb collaterals in the rabbit. The primary findings were that the noninvasively measured (cuff) calf blood pressure rose more in the treated animals, that visual angiographic scores increased, and that capillary density increased. Angiograms showed corkscrew-type collaterals suggestive of muscular arteries, which is somewhat unexpected for an endothelium-specific mitogen.

In a follow-up paper, the Isner group measured flow velocity with a Doppler guide wire in the iliac artery.¹¹⁰ Maximal vasodilation was induced by papaverine, but the dilatory reserve was only barely higher after VEGF treatment than in untreated controls.

	Limits of Collateral Growth

Top Introduction Collaterals Develop by Mitotic... Growth Factors, Their Receptors,... Inhibitors of Vascular Growth Role of Hypoxia Angiogenesis and Vasculogenesis Remodeling of Epicardial... Influence of Shear Stress Quantification of Collateral... Therapeutic Angiogenesis Limits of Collateral Growth Summary and Conclusions References

 
Although the rate of growth of epicardial collaterals stimulated by ischemia alone is impressive, collaterals cannot functionally restore the maximal bulk flow of the artery before its occlusion. In a canine model of ameroid occlusion of the LCX plus the right coronary artery (where the LAD was the only remaining patent artery) collaterals replaced only 30% of the maximal conductance of the artery before occlusion. This is partially due to energy losses created by the tortuous "corkscrew" structure of collaterals that grow not only in radial directions but also in longitudinal directions just as during embryonic life.⁷⁷

Under clinical conditions, another confounding factor should not be overlooked: Often the feeder artery (ie, the artery from which collaterals originate) becomes eventually occluded itself, and even if a new network of collaterals develops from the last remaining patent artery, the pressure head for tissue perfusion becomes greatly reduced. In such a situation even effective gene therapy may not be of great help. Vasculogenesis, the development of large muscular arteries, is needed in advanced coronary artery disease and not angiogenesis.

	Summary and Conclusions

Top Introduction Collaterals Develop by Mitotic... Growth Factors, Their Receptors,... Inhibitors of Vascular Growth Role of Hypoxia Angiogenesis and Vasculogenesis Remodeling of Epicardial... Influence of Shear Stress Quantification of Collateral... Therapeutic Angiogenesis Limits of Collateral Growth Summary and Conclusions References

 
Collateral vessels in the heart (but also those in the limb circulation and probably in all other vascular beds) can reduce the often fatal consequences of large vessel occlusion. They respond by migration and mitosis of endothelial cells in the case of angiogenesis and with mitosis of endothelial cells and smooth muscle cells in the case of in situ enlargement of preexisting connecting arterioles that also undergo profound remodeling (recapitulated vasculogenesis). These processes are certainly triggered by the expression and actions of peptide growth factors, notably by VEGF, aFGF, bFGF, PDGF, and IGF-1. Although the expression of these growth factors was studied extensively in in vitro systems, their temporal and spatial expression in a complex tissue of a relevant animal model is still largely missing.⁶

Controversies still exist as to whether angiogenesis depends exclusively on the increased supply of these growth factors or whether their receptors also need upregulation by the underlying pathological situation that is often associated with inflammation in which monocytes/macrophages play an important role as producers of growth factors and of cytokines. The expression of growth factors in normal hearts in the absence of proliferation suggests the presence of inhibitors. At least two inhibitors of angiogenesis are present in normal heart, ie, TGF-ß and BTG1, and the hypothesis is put forth that three elements of control are required for vascular growth in the heart: growth factor supply, active receptors, and downregulated inhibitors.

Therapeutic angiogenesis was recently attempted in animals with occluded arteries by injection of peptide growth factors; although the majority of these experiments showed interesting trends, several observations remain unexplained (ie, the growth of smooth muscle under the influence of an endothelial mitogen) and some remain controversial. However, there is little doubt that stimulation of angiogenesis by peptides, drugs, or somatic gene therapy will have a place in the near future in the therapy of degenerative vascular disease.

	Selected Abbreviations and Acronyms

 

aFGF = acidic fibroblast growth factor bFGF = basic fibroblast growth factor FLK = fetal liver kinase-1 FLT1 = fms-like–tyrosine kinase-1 IGF-I = insulin-like growth factor I LAD = left anterior descending artery LCX = left circumflex coronary artery LDH = lactate dehydrogenase PAI-1 = platelet activator inhibitor 1 PDGF = platelet-derived growth factor TNF- = tumor necrosis factor- VEGF = vascular endothelial growth factor

	Acknowledgments

 
We thank Prof Dr Werner Risau for suggestions and for critically reading the manuscript and Dr Dimitri Scholz who provided the electron micrographs and immunohistochemical preparations.

Received September 12, 1995; accepted July 7, 1996.

	References

Top Introduction Collaterals Develop by Mitotic... Growth Factors, Their Receptors,... Inhibitors of Vascular Growth Role of Hypoxia Angiogenesis and Vasculogenesis Remodeling of Epicardial... Influence of Shear Stress Quantification of Collateral... Therapeutic Angiogenesis Limits of Collateral Growth Summary and Conclusions References

 
1. Fulton WFM. The Coronary Arteries. Springfield, Ill: Charles C Thomas Publishers; 1965.

2. Spalteholz W. Die Koronararterien des Herzens. Verhandl Anat Ges. 1907;21:141; in Anat Anz 30.

3. Schaper W, DeBrabander M, Lewi P. DNA-synthesis and mitoses in coronary collateral vessels of the dog. Circ Res. 1971;28:671-679.[Abstract/Free Full Text]

4. Schaper W, Pasyk S. Influence of collateral flow on the ischemic tolerance of the heart following acute and subacute coronary occlusion. Circulation. 1976;53(suppl I):I-57-I-62. Abstract.

5. Schaper W, Schaper J. Collateral Circulation: Heart, Brain, Kidney, Limbs. London, UK: Kluwer Academic Publishers; 1993.

6. Ferrara N, Houck K, Jakeman L, Leung DW. Molecular and biological properties of the vascular endothelial growth factor family of proteins. Endocr Rev. 1992;13:18-42.[Abstract/Free Full Text]

7. Klagsbrun M, D'Amore PA. Regulators of angiogenesis. Annu Rev Physiol. 1991;53:217-239.[Medline] [Order article via Infotrieve]

8. Pepper MS, Montesano R. Proteolytic balance and capillary morphogenesis. Cell Differ Dev. 1990;32:319-327.[Medline] [Order article via Infotrieve]

9. Sharma HS, Sassen L, Knoll R, Verdouw PD. Myocardial expression of vascular endothelial growth factor: enhanced transcription during ischemia and reperfusion. Circulation. 1992;86(suppl I):I-1168. Abstract.

10. Connolly D. Vascular permeability factor: a unique regulator of blood vessel function. J Cell Biochem. 1991;47:219-223.[Medline] [Order article via Infotrieve]

11. Ishikawa F, Miyazono K, Hellman U, Drexler H, Wernstedt C, Hagiwara K, Usuki K, Takaku F, Risau W, Heldin C-H. Identification of angiogenic activity and the cloning and expression of platelet-derived endothelial cell growth factor. Nature. 1989;338:557-562.[Medline] [Order article via Infotrieve]

12. Engelmann GL, Dionne CA, Jaye MC. Acidic fibroblast growth factor and heart development: role in myocyte proliferation and capillary angiogenesis. Circ Res. 1993;72:7-19.[Abstract/Free Full Text]

13. Leung DW, Cachlanes G, Kuang WJ, Goeddel D, Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science. 1990;246:1306-1309.

14. Jakeman LB, Bennett JWGL, Altar CA, Ferrara N. Binding sites for vascular endothelial growth factor are localized on endothelial cells in adult rat tissues. J Clin Invest. 1992;89:244-253.

15. Peters KG, Vries CD, Williams LT. Vascular endothelial growth factor receptor expression during embryogenesis and tissue repair suggests a role in endothelial differentiation and blood vessel growth. Proc Natl Acad Sci U S A. 1993;90:8915-8919.[Abstract/Free Full Text]

16. Millauer B, Wizigmann-Voos S, Schnurch H, Martinez R, Moller NPH, Risau W, Ullrich A. High affinity VEGF binding and developmental expression suggest flk-1 as a major regulator of vasculogenesis and angiogenesis. Cell. 1993;72:835-846.[Medline] [Order article via Infotrieve]

17. Shen H, Clauss M, Ryan J, Schmidt A-M, Tijburg P, Borden L, Connolly D, Stern D, Kao J. Characterization of vascular permeability factor/vascular endothelial growth factor receptors on mononuclear phagocytes. Blood. 1993;81:2767-2773.[Abstract/Free Full Text]

18. Clauss M, Gerlach M, Gerlach H, Brett J, Wang F, Familletti PC, Pan Y-CE, Olander JV, Connolly DT, Stern C. Vascular permeability factor: a tumor-derived polypeptide that induces endothelial cell and monocyte procoagulant activity, and promotes monocyte migration. J Exp Med. 1990;172:1535-1545.[Abstract/Free Full Text]

19. Barleon B, Sozzani S, Zhou D, Weich HA, Mantovani A, Marme D. Migration of human monocytes in response to vascular endothelial growth-factor (VEGF) is mediated via the VEGF receptor flt-1. Blood. 1996;87:3336-3343.[Abstract/Free Full Text]

20. Kluge A, Zimmermann R, Munkel B, Mohri M, Sack S, Schaper J, Schaper W. Insulin-like growth factor I is involved in inflammation linked angiogenic processes after microembolisation in porcine heart. Cardiovasc Res. 1995;29:407-415.[Medline] [Order article via Infotrieve]

21. Bernotat-Danielowski S, Sharma H, Schott R, Schaper W. Generation and localisation of monoclonal antibodies against fibroblast growth factors in ischaemic collateralised porcine myocardium. Cardiovasc Res. 1993;27:1220-1228.[Medline] [Order article via Infotrieve]

22. Polverini PJ, Cotran RS, Gimbrone MA, Unanue ER. Activated macrophages induce vascular proliferation. Nature. 1977;269:804-806.[Medline] [Order article via Infotrieve]

23. Berse B, Brown LF, Water LVD, Dvorak HF, Dvorak F, Senger DR. Vascular permeability factor (vascular endothelial growth factor) gene is expressed differentially in normal tissues, macrophages and tumors. Mol Biol Cell. 1992;3:211-220.[Abstract]

24. Wahl SM, Hunt DA, Wakefield LM, McCartney-Francis N, Wahl LM, Roberts AB, Sporn MB. Transforming growth factor type ß induces monocyte chemotaxis and growth factor production. Proc Natl Acad Sci U S A. 1987;84:5788-5792.[Abstract/Free Full Text]

25. Iijima Z, Yoshikawa N, Connolly DT, Nakamura H. Human mesangial cells and peripheral blood mononuclear cells produce vascular permeability factor. Kidney Int. 1993;44:959-966.[Medline] [Order article via Infotrieve]

26. Goto F, Goto K, Weindel K, Folkman J. Synergistic effects of vascular endothelial growth factor and basic fibroblast growth factor on the proliferation and cord formation of bovine capillary endothelial cells within collagen gels. Lab Invest. 1993;69:508-517.[Medline] [Order article via Infotrieve]

27. Rak JW, St Croix BD, Kerbel RS. Consequences of angiogenesis for tumor progression, metastasis and cancer therapy. Anticancer Drugs. 1995;6:3-18.[Medline] [Order article via Infotrieve]

28. Warren RS, Yuan H, Matli MR, Gillett NA, Ferrara N. Regulation by vascular endothelial growth factor of human colon cancer tumorigenesis in a mouse model of experimental liver metastasis. J Clin Invest. 1995;95:1789-1797.

29. Tuder RM, Flook BE, Voelkel NF. Increased gene expression for VEGF and the VEGF receptors KDR/Flk and Flt in lungs exposed to acute or to chronic hypoxia: modulation of gene expression by nitric oxide. J Clin Invest. 1995;95:1798-1807.

30. Plate KH, Breier G, Weich HA, Risau W. Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature. 1992;359:845-848.[Medline] [Order article via Infotrieve]

31. Westernacher D, Schaper W. A novel heart derived inhibitor of vascular cell proliferation: purification and biological activity. J Mol Cell Cardiol. 1995;27:1535-1543.[Medline] [Order article via Infotrieve]

32. Rouault JP, Rimokh R, Tessa C, Paranhos G, Ffrench M, Duret L, Garoccio M, Germain D, Samarut J, Magaud JP. BTG1, a member of a new family of antiproliferative genes. EMBO J. 1992;11:1663-1670.[Medline] [Order article via Infotrieve]

33. Folkman J. Tumor Angiogenesis. Philadelphia, Pa: WB Saunders Co; 1995.

34. Jackson D, Volpert OV, Bouck N, Linzer DIH. Stimulation and inhibition of angiogenesis by placental proliferin and proliferin-related protein. Science. 1994;266:1581-1584.[Abstract/Free Full Text]

35. Clapp C, Martial JA, Guzman RC, Rentier-Delure F, Weiner RI. The 16-kilodalton N-terminal fragment of human prolactin is a potent inhibitor of angiogenesis. Endocrinology. 1993;133:1292-1299.[Abstract/Free Full Text]

36. Hanneken A, Ying W, Ling N, Baird A. Identification of soluble forms of the fibroblast growth factor receptor in blood. Proc Natl Acad Sci U S A. 1994;91:9170-9174.[Abstract/Free Full Text]

37. Banai S, Shweiki D, Pinson A, Chandra M, Lazarovici G, Keshet E. Upregulation of vascular endothelial growth factor expression induced by myocardial ischaemia: implications for coronary angiogenesis. Cardiovasc Res. 1994;28:1176-1179.[Abstract/Free Full Text]

38. Stavri GR, Hong Y, Zachary IC, Breier GB, Baskerville PA, Yla-Herttuala S, Risau W, Martin JF, Erusalimsky JD. Hypoxia and platelet-derived growth factor-BB synergistically upregulate the expression of vascular endothelial growth factor in vascular smooth muscle cells. FEBS Lett. 1995;358:311-315.[Medline] [Order article via Infotrieve]

39. Shweiki D, Itin A, Soffer D, Keshet E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature. 1992;359:843-845.[Medline] [Order article via Infotrieve]

40. Hashimoto E, Ogita T, Nakaoka T, Matsuoka R, Takao A, Kirka Y. Rapid induction of vascular endothelial growth factor expression by transient ischemia in rat heart. Am J Physiol. 1994;267:H1948-H1954.[Abstract/Free Full Text]

41. Ladoux A, Frelin C. Hypoxia is a strong inducer of vascular endothelial growth factor mRNA expression in the heart. Biochem Biophys Res Commun. 1993;195:1005-1010.[Medline] [Order article via Infotrieve]

42. Levy AP, Levy NS, Loscalzo J, Calderone A, Takahashi N, Yeo K-T, Koren D, Colucci WS, Goldberg MA. Regulation of vascular endothelial growth factor in cardiac myocytes. Circ Res. 1995;76:758-766.[Abstract/Free Full Text]

43. Fujita M, McKown DP, McKown MD, Franklin D. Changes in coronary flow following repeated brief coronary occlusion in the conscious dog. Heart Vessels. 1986;2:87-90.[Medline] [Order article via Infotrieve]

44. Ikeda E, Achen MG, Breier G, Risau W. Hypoxia-induced transcriptional activation and increased mRNA stability of vascular endothelial growth factor in C6 glioma cells. J Biol Chem. 1995;270:19761-19766.[Abstract/Free Full Text]

45. Fischer S, Sharma HS, Karliczek GF, Schaper W. Expression of vascular permeability factor/vascular endothelial growth factor in pig cerebral microvascular endothelial cells and its upregulation by adenosine. Mol Brain Res. 1995;28:141-148.[Medline] [Order article via Infotrieve]

46. Sparks HV Jr, Bardenheuer H. Regulation of adenosine formation by the heart. Circ Res. 1986;58:193-201.[Abstract/Free Full Text]

47. Yang HT, Ogilvie RW, Terjung RL. Peripheral adaptations in trained aged rats with femoral artery stenosis. Circ Res. 1994;74:235-243.[Abstract/Free Full Text]

48. Arras M, Mohri M, Sack S, Schwarz ER, Schaper J, Schaper W. Macrophages accumulate and release tumor necrosis factor-alpha in the ischemic porcine myocardium. Circulation. 1992;86(suppl I):I-129. Abstract.

49. Leibovich SJ, Ross R. The role of the macrophage in wound repair: a study with hydrocortisone and antimacrophage serum. Am J Pathol. 1975;78:71-100.[Abstract]

50. Dumont DJ, Fong G-H, Puri MC, Gradwohl G, Alitalo D, Breitman ML. Vascularization of the mouse embryo: a study of flk-1, tek, tie, and vascular endothelial growth factor expression during development. Dev Dyn. 1995;203:80-92.[Medline] [Order article via Infotrieve]

51. Risau W, Flamme I. Vasculogenesis. Annu Rev Cell Dev Biol. 1995;11:73-91.[Medline] [Order article via Infotrieve]

52. Gorge G, Ito BR, Pantely GA, Schaper W. Effects of chronic coronary artery stenosis on collateral development in swine. J Mol Cell Cardiol. 1986;18(suppl II):11. Abstract.

53. O'Konski MS, White FC, Longhurst JC, Roth D, Bloor CM. Ameroid constriction of the proximal left circumflex coronary artery in swine. Am J Cardiovasc Pathol. 1986;1:69-77.

54. Roth DM, Maruoka Y, Rogers J, White FC, Longhurst JC, Bloor CM. Development of coronary collateral circulation in left circumflex ameroid-occluded swine myocardium. Am J Physiol. 1987;253:H1279-H1288.[Abstract/Free Full Text]

55. White FC, Carroll SM, Magnet A, Bloor CM. Coronary collateral development in swine after coronary artery occlusion. Circ Res. 1992;71:1490-1500.[Abstract/Free Full Text]

56. Roth DM, White FC, Bloor CM. Altered minimal coronary resistance to antegrade reflow after chronic coronary artery occlusion in swine. Circ Res. 1988;63:330-339.[Abstract/Free Full Text]

57. Schaper J, Konig R, Franz D, Schaper W. The endothelial surface of growing coronary collateral arteries: intimal margination and diapedesis of monocytes—a combined SEM and TEM study. Virchows Arch A Pathol Anat Histol. 1976;370:193-205.[Medline] [Order article via Infotrieve]

58. Chilian WM, Mass HJ, Williams SE, Layne SM, Smith ES, Scheel KW. Microvascular occlusions promote coronary collateral growth. Am J Physiol. 1990;258:H1103-H1111.[Abstract/Free Full Text]

59. Bloor CM, White FC, Sanders TM. Effects of exercise on collateral development in myocardial ischemia in pigs. J Appl Physiol. 1984;56:656-665.[Abstract/Free Full Text]

60. White FC, Roth DM, Bloor CM. The pig as a model for myocardial ischemia and exercise. Lab Anim Sci. 1986;36:351-356.[Medline] [Order article via Infotrieve]

61. Roth DM, White FC, Nichols ML, Dobbs SL, Longhurst JC, Bloor CM. Effect of long-term exercise on regional myocardial function and coronary collateral development after gradual coronary artery occlusion in pigs. Circulation. 1990;82:1778-1789.[Abstract/Free Full Text]

62. Breisch EA, White FC, Nimmo LA, McKirnan MD, Bloor CM. Exercise-induced cardiac hypertrophy: a correlation of blood flow and microvasculature. J Appl Physiol. 1986;60:1259-1267.[Abstract/Free Full Text]

63. Schaper W. Influence of physical exercise on coronary collateral blood flow in chronic experimental two-vessel occlusion. Circulation. 1982;65:905-912.[Abstract/Free Full Text]

64. Pasyk S, Schaper W, Schaper J, Pasyk K, Miskiewicz G, Steinseifer B. DNA synthesis in coronary collaterals after coronary artery occlusion in conscious dog. Am J Physiol. 1982;242:H1031-H1037.

65. Dvorak HF, Brown LF, Detmar M, Dvorak AM. Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability and angiogenesis. Am J Pathol. 1995;146:1029-1039.[Abstract]

66. Majano G, Joris I. Apoptosis, oncosis, and necrosis: an overview of cell death. Am J Pathol. 1995;146:3-15.[Abstract]

67. Reed JC. Bcl-2 and the regulation of programmed cell death. J Cell Biol. 1994;124:1-6.[Free Full Text]

68. Pepper MS, Belin D, Montesano R, Orci L, Vassalli JD. Transforming growth factor beta 1 modulates basic fibroblast growth factor induced proteolytic and angiogenic properties of endothelial cells in vitro. J Cell Biol. 1990;111:743-753.[Abstract/Free Full Text]

69. Pepper MS, Vassalli JD, Montesano R, Orci L. Urokinase-type plasminogen activator is induced in migrating capillary endothelial cells. J Cell Biol. 1987;105:2535-2541.[Abstract/Free Full Text]

70. Knoepfler PS, Bloor CM, Carroll SM. Urokinase plasminogen activator activity is increased in the myocardium during coronary artery occlusion. J Mol Cell Cardiol. 1995;27:1317-1324.[Medline] [Order article via Infotrieve]

71. Konkle BA, Ginsburg D. The addition of endothelial cell growth factor and heparin to human umbilical vein endothelial cell cultures decreases plasminogen activator inhibitor-1 expression. J Clin Invest. 1988;82:579-585.

72. Saksela O, Moscatelli D, Rifkin B. The opposing effects of basic fibroblast growth factor and transforming growth factor beta on the regulation of plasminogen activator activity in capillary endothelial cells. J Cell Biol. 1987;105:957-963.[Abstract/Free Full Text]

73. Mandriota SJ, Seghezzi G, Vassalli JD, Ferrara N, Wasi S, Mazzieri R, Mignatti P, Pepper MS. Vascular endothelial growth factor increases urokinase receptor expression in vascular endothelial cells. J Biol Chem. 1995;270:9709-9716.[Abstract/Free Full Text]

74. Mignatti P, Tsuboi R, Robbins E, Rifkin DB. In vitro angiogenesis on the human amniotic membrane: requirement for basic fibroblast growth factor-induced proteinases. J Cell Biol. 1989;108:571-682.

75. Flaumenhaft R, Abe M, Mignatti P, Rifkin DB. Basic fibroblast growth factor-induced activation of latent transforming growth factor ß in endothelial cells: regulation of plasminogen activator activity. J Cell Biol. 1992;118:901-909.[Abstract/Free Full Text]

76. Schaper W. Collateral circulation, I: collaterals in chronic coronary occlusion. In: Schaper W, ed. The Pathophysiology of Myocardial Perfusion. Amsterdam, Netherlands: Elsevier/North-Holland Biomedical Press; 1979:415-436.

77. Schaper W. Collateral anatomy and blood flow: its potential role in sudden coronary death. Ann N Y Acad Sci. 1982;382:69-74.[Medline] [Order article via Infotrieve]

78. Schaper J, Weihrauch D. Collateral vessel development in the porcine and canine heart. In: Schaper W, Schaper J, eds. Collateral Circulation: Heart, Brain, Kidney, Limbs. Dordrecht, Netherlands: Kluwer Academic Publishers; 1993:65-102.

79. Hacking WJG, VanBavel E, Spaan JAE. Shear stress is not sufficient to control growth of vascular networks: a model study. Am J Physiol. 1996;270:H364-H375.[Abstract/Free Full Text]

80. Geary RL, Kohler TR, Vergel S, Kirkman TR, Clowes AW. Time course of flow-induced smooth muscle cell proliferation and intimal thickening in endothelialized baboon vascular grafts. Circ Res. 1993;74:14-23.[Abstract/Free Full Text]

81. Malek AM, Gibbons GH, Dzau VJ, Izumo S. Fluid shear stress differentially modulates expression of genes encoding basic fibroblast growth factor and platelet-derived growth factor B chain in vascular endothelium. J Clin Invest. 1993;92:2013-2021.

82. Mitsumata M, Fishel RS, Nerem RM, Alexander RW, Berk BC. Fluid shear stress stimulates platelet-derived growth factor expression in endothelial cells. Am J Physiol. 1993;150:552-558.

83. Hsieh HJ, Li NQ, Frangos JA. Shear stress increases endothelial platelet-derived growth factor mRNA levels. Am J Physiol. 1991;260:H642-H646.[Abstract/Free Full Text]

84. Hsieh HJ, Li NQ, Frangos JA. Shear-induced platelet-derived growth factor gene expression in human endothelial cells is mediated by protein kinase C. J Cell Physiol. 1992;150:552-558.[Medline] [Order article via Infotrieve]

85. Thoma R. Untersuchungen uber die Histogenese und Histomechanik des Gefaßsystems. Stuttgart, Germany: F. Enke; 1893.

86. Schaper W. The Collateral Circulation of the Heart. Amsterdam, Netherlands: Elsevier North Holland Publishing Company; 1971.

87. Nagel T, Resnick N, Atkinson W, Dewey WJ, Gimbrone CF. Shear stress upregulates functional ICAM-1 expression in cultured vascular endothelial cells. FASEB J. 1993;7:A2. Abstract.

88. Sampath R, Kukielka GL, Smith CW, Eskin SG, McIntire LV. Shear stress-mediated changes in the expression of leukocyte adhesion receptors on human umbilical vein endothelial cells in vitro. Ann Biomed Eng. 1995;23:247-256.[Medline] [Order article via Infotrieve]

89. Ando J, Normura H, Kamiya A. The effect of fluid shear stress on the migration and proliferation of cultured endothelial cells. Microvascular Res. 1987;33:62-70.[Medline] [Order article via Infotrieve]

90. Patrick CW, McIntire LV. Shear stress and cyclic strain modulation of gene expression in vascular endothelial cells. Blood Purif. 1995;13:112-124.[Medline] [Order article via Infotrieve]

91. Ohno M, Lopez F, Gibbons GH, Cooke JP, Dzau VJ. Shear stress induced TGFß1 gene expression and generation of active TGFß1 is mediated via a K⁺-channel. Circulation. 1992;86(suppl I):I-87. Abstract.

92. Noris M, Morigi M, Conadelli R, Aiello S, Foppolo M, Todeschini M, Orisio S, Remuzzi G, Remuzzi A. Nitric oxide synthesis by cultured endothelial cells is modulated by flow conditions. Circ Res. 1995;76:536-543.[Abstract/Free Full Text]

93. Kourembanas S, Mcquillan LP, Leung GK, Faller DV. Nitric oxide regulates the expression of vasoconstrictors and growth factors by vascular endothelium under both normoxia and hypoxia. J Clin Invest. 1993;92:99-104.

94. Zeiher AM, Fisslthaler B, Schray-Utz B, Busse R. Nitric oxide modulates the expression of monocyte chemoattractant protein 1 in cultured human endothelial cells. Circ Res. 1995;76:980-986.[Abstract/Free Full Text]

95. Borgers M, Schaper J, Schaper W. Acute vascular lesions in developing coronary collaterals. Virchows Arch Pathol Anat Physiol Klin Med. 1970;351:1-11.[Medline] [Order article via Infotrieve]

96. Schaper W, Flameng W, Winkler B, Wuesten B, Turschmann W, Neugebauer G, Carl M, Pasyk S. Quantification of collateral resistance in acute and chronic experimental coronary occlusion in the dog. Circ Res. 1976;39:371-377.[Abstract/Free Full Text]

97. Banai S, Jaklitsch MT, Shou M, Lazarous DF, Scheinowitz M, Biro S, Epstein SE, Unger EF. Angiogenic-induced enhancement of collateral blood flow to ischemic myocardium by vascular endothelial growth factor in dogs. Circulation. 1994;89:2183-2189.[Abstract/Free Full Text]

98. Cuevas P, Gonzalez AM, Carceller F, Baird A. Vascular response to basic fibroblast growth factor when infused onto the normal adventitia or into the injured media of the rat carotid artery. Circ Res. 1991;69:360-369.[Abstract/Free Full Text]

99. Kass RW, Kotler MN, Yazdanfar S. Stimulation of coronary collateral growth: current developments in angiogenesis and future clinical applications. Am Heart J. 1991;123:486-496.

100. Leclerc G, Gal D, Takeshita S, Nikol S, Weir L, Isner JM. Percutaneous arterial gene transfer in a rabbit model: efficiency in normal and balloon-dilated atherosclerotic arteries. J Clin Invest. 1992;90:936-944.

101. Nabel EG, Yang Z-Y, Plautz G, Forough R, Zhan X, Haudenschild CC, Maciag T, Nabel GJ. Recombinant fibroblast growth factor-1 promotes intimal hyperplasia and angiogenesis in arteries in vivo. Nature. 1993;362:844-846.[Medline] [Order article via Infotrieve]

102. Nabel EG, Yang Z, Liptay S, San H, Gordon D, Haudenschild CC. Recombinant platelet-derived growth factor B gene expression in porcine arteries induces intimal hyperplasia in vivo. J Clin Invest. 1993;91:1822-1829.

103. Harada K, Grossman W, Friedman M, Edelman ER, Prasad PV, Keighley CS, Manning WJ, Sellke FW, Simons M. Basic fibroblast growth factor improves myocardial function in chronically ischemic porcine hearts. J Clin Invest. 1994;94:623-630.

104. Takeshita S, Zheng LP, Brogi E, Kearney M, Pu L-Q, Bunting S, Ferrara N, Symes JF, Isner JM. Therapeutic angiogenesis: a single intraarterial bolus of vascular endothelial growth factor augments revascularization in a rabbit ischemic hind limb model. J Clin Invest. 1994;93:662-670.

105. Unger EF, Banai S, Shou M, Lazarous DF, Jaklitsch MT, Sheinowitz M, Correa R, Klingbeil C, Epstein SE. Basic fibroblast growth factor enhances myocardial collateral flow in a canine model. Am J Physiol. 1994;266:H1588-H1595.[Abstract/Free Full Text]

106. Yanagisawa-Miwa K, Ushida Y, Nakamura F, Tomaru T, Kido H, Kamijo T, Sugimoto T, Kaji K, Utsuyama M, Kurashima C, Ito H. Salvage of infarcted myocardium by angiogenic action of basic fibroblast growth factor. Science. 1992;257:1401-1403.[Abstract/Free Full Text]

107. Lazarous DF, Scheinowitz M, Shou M, Hodge E, Rajanayagam S, Hunsberger S, Robinson WGJ, Stiber JA, Correa R, Epstein SE. Effects of chronic systemic administration of basic fibroblast growth factor on collateral development in the canine heart. Circulation. 1995;91:145-153.[Abstract/Free Full Text]

108. Baird A, Walicke P. Fibroblast growth factors. Br Med Bull. 1989;45:438-452.[Abstract/Free Full Text]

109. Scheinowitz M, Shou M, Banai S, Gertz SD, Lazarous DF, Unger EF. Neointimal proliferation in canine coronary arteries: a model of restenosis permitting local and continuous drug delivery. Lab Invest. 1994;71:813-819.[Medline] [Order article via Infotrieve]

110. Bauters C, Asahara T, Zheng LP, Takeshita S, Bunting S, Ferrara N, Symes JF, Isner JM. Physiological assessment of augmented vascularity induced by VEGF in ischemic rabbit hindlimb. Am J Physiol. 1994;267:H1263-H1271.[Abstract/Free Full Text]

This article has been cited by other articles:

				R. A. Benndorf, E. Schwedhelm, A. Gnann, R. Taheri, G. Kom, M. Didie, A. Steenpass, S. Ergun, and R. H. Boger Isoprostanes Inhibit Vascular Endothelial Growth Factor-Induced Endothelial Cell Migration, Tube Formation, and Cardiac Vessel Sprouting In Vitro, As Well As Angiogenesis In Vivo via Activation of the Thromboxane A2 Receptor: A Potential Link Between Oxidative Stress and Impaired Angiogenesis Circ. Res., October 24, 2008; 103(9): 1037 - 1046. [Abstract] [Full Text] [PDF]

				T. Kinnaird, E. Stabile, S. Zbinden, M.-S. Burnett, and S. E. Epstein Cardiovascular risk factors impair native collateral development and may impair efficacy of therapeutic interventions Cardiovasc Res, May 1, 2008; 78(2): 257 - 264. [Abstract] [Full Text] [PDF]

				S. Celik, S. Kaplan, R. Yilmaz, T. Erdogan, and A. Kiris Relationship Between Aortic Stiffness and the Development of Coronary Collateral in Patients With Coronary Artery Disease Angiology, January 1, 2008; 58(6): 671 - 676. [Abstract] [PDF]

				C. E. Bergmann, I. E. Hoefer, B. Meder, H. Roth, N. van Royen, S. M. Breit, M. M. Jost, S. Aharinejad, S. Hartmann, and I. R. Buschmann Arteriogenesis depends on circulating monocytes and macrophage accumulation and is severely depressed in op/op mice J. Leukoc. Biol., July 1, 2006; 80(1): 59 - 65. [Abstract] [Full Text] [PDF]

				W.-C. Shyu, S.-Z. Lin, M.-F. Chiang, C.-Y. Su, and H. Li Intracerebral peripheral blood stem cell (CD34+) implantation induces neuroplasticity by enhancing beta1 integrin-mediated angiogenesis in chronic stroke rats. J. Neurosci., March 29, 2006; 26(13): 3444 - 3453. [Abstract] [Full Text] [PDF]

				R. Vogel, R. Zbinden, A. Indermuhle, S. Windecker, B. Meier, and C. Seiler Collateral-flow measurements in humans by myocardial contrast echocardiography: validation of coronary pressure-derived collateral-flow assessment Eur. Heart J., January 2, 2006; 27(2): 157 - 165. [Abstract] [Full Text] [PDF]

				E. Toyota, D. C. Warltier, T. Brock, E. Ritman, C. Kolz, P. O'Malley, P. Rocic, M. Focardi, and W. M. Chilian Vascular Endothelial Growth Factor Is Required for Coronary Collateral Growth in the Rat Circulation, October 4, 2005; 112(14): 2108 - 2113. [Abstract] [Full Text] [PDF]

				J. E. Markkanen, T. T. Rissanen, A. Kivela, and S. Yla-Herttuala Growth factor-induced therapeutic angiogenesis and arteriogenesis in the heart-gene therapy Cardiovasc Res, February 15, 2005; 65(3): 656 - 664. [Abstract] [Full Text] [PDF]

				M. Voskuil, I. E Hoefer, N. van Royen, J. Hua, S. de Graaf, C. Bode, I. R Buschmann, and J. J Piek Abnormal monocyte recruitment and collateral artery formation in monocyte chemoattractant protein-1 deficient mice Vascular Medicine, November 1, 2004; 9(4): 287 - 292. [Abstract] [PDF]

				E. R. Schwarz, D. A. Meven, N. Z. Sulemanjee, P. H. Kersting, T. Tussing, E. C. Skobel, P. Hanrath, and B. F. Uretsky Monocyte Chemoattractant Protein 1-Induced Monocyte Infiltration Produces Angiogenesis but Not Arteriogenesis in Chronically Infarcted Myocardium Journal of Cardiovascular Pharmacology and Therapeutics, October 1, 2004; 9(4): 279 - 289. [Abstract] [PDF]

				P. Schalch, G. Patejunas, M. Retuerto, S. Sarateanu, J. Milbrandt, G. Thakker, D. Kim, J. Carbray, R. G. Crystal, and T. K. Rosengart Homozygous deletion of early growth response 1 gene and critical limb ischemia after vascular ligation in mice: Evidence for a central role in vascular homeostasis J. Thorac. Cardiovasc. Surg., October 1, 2004; 128(4): 595 - 601. [Abstract] [Full Text] [PDF]

				T. Kinnaird, E. Stabile, M. S. Burnett, and S. E. Epstein Bone Marrow-Derived Cells for Enhancing Collateral Development: Mechanisms, Animal Data, and Initial Clinical Experiences Circ. Res., August 20, 2004; 95(4): 354 - 363. [Abstract] [Full Text] [PDF]

				N. Hattan, D. Warltier, W. Gu, C. Kolz, W. M. Chilian, and D. Weihrauch Autologous vascular smooth muscle cell-based myocardial gene therapy to induce coronary collateral growth Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H488 - H493. [Abstract] [Full Text] [PDF]

				J. L. Unthank, K. M. Sheridan, and M. C. Dalsing Collateral Growth in the Peripheral Circulation: A Review Vascular and Endovascular Surgery, July 1, 2004; 38(4): 291 - 313. [Abstract] [PDF]

				V. R. Panchal, J. Rehman, A. T. Nguyen, J. W. Brown, M. W. Turrentine, Y. Mahomed, and K. L. March Reduced pericardial levels of endostatin correlate with collateral development in patients with ischemic heart disease J. Am. Coll. Cardiol., April 21, 2004; 43(8): 1383 - 1387. [Abstract] [Full Text] [PDF]

				T. Kinnaird, E. Stabile, M.S. Burnett, C.W. Lee, S. Barr, S. Fuchs, and S.E. Epstein Marrow-Derived Stromal Cells Express Genes Encoding a Broad Spectrum of Arteriogenic Cytokines and Promote In Vitro and In Vivo Arteriogenesis Through Paracrine Mechanisms Circ. Res., March 19, 2004; 94(5): 678 - 685. [Abstract] [Full Text] [PDF]

				J. Rutanen, T. T. Rissanen, J. E. Markkanen, M. Gruchala, P. Silvennoinen, A. Kivela, A. Hedman, M. Hedman, T. Heikura, M.-R. Orden, et al. Adenoviral Catheter-Mediated Intramyocardial Gene Transfer Using the Mature Form of Vascular Endothelial Growth Factor-D Induces Transmural Angiogenesis in Porcine Heart Circulation, March 2, 2004; 109(8): 1029 - 1035. [Abstract] [Full Text] [PDF]

				H. Tomoda and N. Aoki Coronary Blood Flow in Evolving Myocardial Infarction Preceded by Preinfarction Angina: A Critical Reevaluation of Preconditioning Effects in Clinical Cases Angiology, January 1, 2004; 55(1): 9 - 15. [Abstract] [PDF]

				M. Dixit, D. Zhuang, B. Ceacareanu, and A. Hassid Treatment With Insulin Uncovers the Motogenic Capacity of Nitric Oxide in Aortic Smooth Muscle Cells: Dependence on Gab1 and Gab1-SHP2 Association Circ. Res., November 14, 2003; 93 (10): e113 - e123. [Abstract] [Full Text] [PDF]

				E. VanBavel, P. Siersma, and J. A. E. Spaan Elasticity of passive blood vessels: a new concept Am J Physiol Heart Circ Physiol, November 1, 2003; 285(5): H1986 - H2000. [Abstract] [Full Text] [PDF]

				J. Koerselman, Y. van der Graaf, P. P.Th. de Jaegere, and D. E. Grobbee Coronary Collaterals: An Important and Underexposed Aspect of Coronary Artery Disease Circulation, May 20, 2003; 107(19): 2507 - 2511. [Full Text] [PDF]

				G. C. Hughes, M. J. Post, M. Simons, and B. H. Annex Translational Physiology: Porcine models of human coronary artery disease: implications for preclinical trials of therapeutic angiogenesis J Appl Physiol, May 1, 2003; 94(5): 1689 - 1701. [Abstract] [Full Text] [PDF]

				S. G. Nir, R. David, M. Zaruba, W.-M. Franz, and J. Itskovitz-Eldor Human embryonic stem cells for cardiovascular repair Cardiovasc Res, May 1, 2003; 58(2): 313 - 323. [Abstract] [Full Text] [PDF]

				G. S. Werner, M. Ferrari, S. Heinke, F. Kuethe, R. Surber, B. M. Richartz, and H. R. Figulla Angiographic Assessment of Collateral Connections in Comparison With Invasively Determined Collateral Function in Chronic Coronary Occlusions Circulation, April 22, 2003; 107(15): 1972 - 1977. [Abstract] [Full Text] [PDF]

				A. Roguin, A. Avivi, S. Nitecki, I. Rubinstein, N. S. Levy, Z. A. Abassi, M. B. Resnick, O. Lache, M. Melamed-Frank, A. Joel, et al. Restoration of blood flow by using continuous perimuscular infiltration of plasmid DNA encoding subterranean mole rat Spalax ehrenbergi VEGF PNAS, April 15, 2003; 100(8): 4644 - 4648. [Abstract] [Full Text] [PDF]

				M. Voskuil, N. van Royen, I. E. Hoefer, R. Seidler, B. D. Guth, C. Bode, W. Schaper, J. J. Piek, and I. R. Buschmann Modulation of collateral artery growth in a porcine hindlimb ligation model using MCP-1 Am J Physiol Heart Circ Physiol, April 1, 2003; 284(4): H1422 - H1428. [Abstract] [Full Text] [PDF]

				F. Pipp, M. Heil, K. Issbrucker, T. Ziegelhoeffer, S. Martin, J. van den Heuvel, H. Weich, B. Fernandez, G. Golomb, P. Carmeliet, et al. VEGFR-1-Selective VEGF Homologue PlGF Is Arteriogenic: Evidence for a Monocyte-Mediated Mechanism Circ. Res., March 7, 2003; 92(4): 378 - 385. [Abstract] [Full Text] [PDF]

				C. Heeschen, M. Weis, and J. P. Cooke Nicotine promotes arteriogenesis J. Am. Coll. Cardiol., February 5, 2003; 41(3): 489 - 496. [Abstract] [Full Text] [PDF]

				M. Ruel, R. A. Kelly, and F. W. Sellke Therapeutic Angiogenesis, Transmyocardial Laser Revascularization, and Cell Therapy Card. Surg. Adult, January 1, 2003; 2(2003): 715 - 750. [Full Text]

				M. Heil, T. Ziegelhoeffer, F. Pipp, S. Kostin, S. Martin, M. Clauss, and W. Schaper Blood monocyte concentration is critical for enhancement of collateral artery growth Am J Physiol Heart Circ Physiol, December 1, 2002; 283(6): H2411 - H2419. [Abstract] [Full Text] [PDF]

				A. Zakrzewicz, T. W. Secomb, and A. R. Pries Angioadaptation: Keeping the Vascular System in Shape Physiology, October 1, 2002; 17(5): 197 - 201. [Abstract] [Full Text] [PDF]

				Y. Chang, B. Ceacareanu, M. Dixit, N. Sreejayan, and A. Hassid Nitric Oxide-Induced Motility in Aortic Smooth Muscle Cells: Role of Protein Tyrosine Phosphatase SHP-2 and GTP-Binding Protein Rho Circ. Res., September 6, 2002; 91(5): 390 - 397. [Abstract] [Full Text] [PDF]

				J. L. Tuttle, T. L. Hahn, B. M. Sanders, F. A. Witzmann, S. J. Miller, M. C. Dalsing, and J. L. Unthank Impaired collateral development in mature rats Am J Physiol Heart Circ Physiol, July 1, 2002; 283(1): H146 - H155. [Abstract] [Full Text] [PDF]

				G. C. Hughes, S. S. Biswas, B. Yin, D. V. Baklanov, B. H. Annex, R. E. Coleman, T. R. DeGrado, C. K. Landolfo, K. P. Landolfo, and J. E. Lowe A comparison of mechanical and laser transmyocardial revascularization for induction of angiogenesis and arteriogenesis in chronically ischemic myocardium J. Am. Coll. Cardiol., April 3, 2002; 39(7): 1220 - 1228. [Abstract] [Full Text] [PDF]

				L. L. Johnson, S. Thambar, T. Donahay, M. Dae, and D. O. Williams Effect of Endomyocardial Laser Channels on Regional Innervation Shown with 125I-MIBG and Autoradiography J. Nucl. Med., April 1, 2002; 43(4): 551 - 555. [Abstract] [Full Text] [PDF]

				J. Rockstroh and B. G. Brown Coronary Collateral Size, Flow Capacity, and Growth: Estimates From the Angiogram in Patients With Obstructive Coronary Disease Circulation, January 15, 2002; 105(2): 168 - 173. [Abstract] [Full Text] [PDF]

				H. Huwer, C. Welter, C. Ozbek, M. Seifert, U. Straub, P. Greilach, G. Kalweit, and H. Isringhaus Simultaneous surgical revascularization and angiogenic gene therapy in diffuse coronary artery disease Eur. J. Cardiothorac. Surg., December 1, 2001; 20(6): 1128 - 1134. [Abstract] [Full Text] [PDF]

				C. Seiler, T. Pohl, K. Wustmann, D. Hutter, P.-A. Nicolet, S. Windecker, F. R. Eberli, and B. Meier Promotion of Collateral Growth by Granulocyte-Macrophage Colony-Stimulating Factor in Patients With Coronary Artery Disease: A Randomized, Double-Blind, Placebo-Controlled Study Circulation, October 23, 2001; 104(17): 2012 - 2017. [Abstract] [Full Text] [PDF]

				M. Azrin Angiogenesis, protein and gene delivery Br. Med. Bull., October 1, 2001; 59(1): 211 - 225. [Abstract] [Full Text] [PDF]

				D Masuda, R Nohara, T Hirai, K Kataoka, L.G Chen, R Hosokawa, M Inubushi, E Tadamura, M Fujita, and S Sasayama Enhanced external counterpulsation improved myocardial perfusion and coronary flow reserve in patients with chronic stable angina. Evaluation by13N-ammonia positron emission tomography Eur. Heart J., August 2, 2001; 22(16): 1451 - 1458. [Abstract] [PDF]

				B. C. Berk Vascular Smooth Muscle Growth: Autocrine Growth Mechanisms Physiol Rev, July 1, 2001; 81(3): 999 - 1030. [Abstract] [Full Text] [PDF]

				R. J Bing Myocardial ischemia and infarction: growth of ideas Cardiovasc Res, July 1, 2001; 51(1): 13 - 20. [Abstract] [Full Text] [PDF]

				R Tabibiazar and S.G Rockson Angiogenesis and the ischaemic heart Eur. Heart J., June 1, 2001; 22(11): 903 - 918. [PDF]

				S. Tateno, M. Terai, K. Niwa, T. Jibiki, H. Hamada, K. Yasukawa, T. Honda, S. Oana, and Y. Kohno Alleviation of Myocardial Ischemia After Kawasaki Disease by Heparin and Exercise Therapy Circulation, May 29, 2001; 103(21): 2591 - 2597. [Abstract] [Full Text] [PDF]

				I. Kim, S.-O. Moon, C.-Y. Han, Y. K. Pak, S. K. Moon, J. J. Kim, and G. Y. Koh The angiopoietin-tie2 system in coronary artery endothelium prevents oxidized low-density lipoprotein-induced apoptosis Cardiovasc Res, March 1, 2001; 49(4): 872 - 881. [Abstract] [Full Text] [PDF]

				E. M. Conway, D. Collen, and P. Carmeliet Molecular mechanisms of blood vessel growth Cardiovasc Res, February 16, 2001; 49(3): 507 - 521. [Full Text] [PDF]

				J. Waltenberger Impaired collateral vessel development in diabetes: potential cellular mechanisms and therapeutic implications Cardiovasc Res, February 16, 2001; 49(3): 554 - 560. [Abstract] [Full Text] [PDF]

				I. E. Hoefer, N. van Royen, I. R. Buschmann, J. J. Piek, and W. Schaper Time course of arteriogenesis following femoral artery occlusion in the rabbit Cardiovasc Res, February 16, 2001; 49(3): 609 - 617. [Abstract] [Full Text] [PDF]

				T. Matsunaga, D. C. Warltier, D. W. Weihrauch, M. Moniz, J. Tessmer, and W. M. Chilian Ischemia-Induced Coronary Collateral Growth Is Dependent on Vascular Endothelial Growth Factor and Nitric Oxide Circulation, December 19, 2000; 102(25): 3098 - 3103. [Abstract] [Full Text] [PDF]

				R. J. Laham, N. A. Chronos, M. Pike, M. E. Leimbach, J. E. Udelson, J. D. Pearlman, R. I. Pettigrew, M. J. Whitehouse, C. Yoshizawa, and M. Simons Intracoronary basic fibroblast growth factor (FGF-2) in patients with severe ischemic heart disease: results of a Phase I open-label dose escalation study J. Am. Coll. Cardiol., December 1, 2000; 36(7): 2132 - 2139. [Abstract] [Full Text] [PDF]

				J. K. Chae, I. Kim, S. T. Lim, M. J. Chung, W. H. Kim, H. G. Kim, J. K. Ko, and G. Y. Koh Coadministration of Angiopoietin-1 and Vascular Endothelial Growth Factor Enhances Collateral Vascularization Arterioscler. Thromb. Vasc. Biol., December 1, 2000; 20(12): 2573 - 2578. [Abstract] [Full Text] [PDF]

				N. G. Frangogiannis, L. H. Michael, and M. L. Entman Myofibroblasts in reperfused myocardial infarcts express the embryonic form of smooth muscle myosin heavy chain (SMemb) Cardiovasc Res, October 1, 2000; 48(1): 89 - 100. [Abstract] [Full Text] [PDF]

				N. I. Moldovan, P. J. Goldschmidt-Clermont, J. Parker-Thornburg, S. D. Shapiro, and P. E. Kolattukudy Contribution of Monocytes/Macrophages to Compensatory Neovascularization : The Drilling of Metalloelastase-Positive Tunnels in Ischemic Myocardium Circ. Res., September 1, 2000; 87(5): 378 - 384. [Abstract] [Full Text] [PDF]

				B. Fernandez, A. Buehler, S. Wolfram, S. Kostin, G. Espanion, W. M. Franz, H. Niemann, P. A. Doevendans, W. Schaper, and R. Zimmermann Transgenic Myocardial Overexpression of Fibroblast Growth Factor-1 Increases Coronary Artery Density and Branching Circ. Res., August 4, 2000; 87(3): 207 - 213. [Abstract] [Full Text] [PDF]

				H. T. Yang, Y. Feng, L. A. Allen, A. Protter, and R. L. Terjung Efficacy and specificity of bFGF increased collateral flow in experimental peripheral arterial insufficiency Am J Physiol Heart Circ Physiol, June 1, 2000; 278(6): H1966 - H1973. [Abstract] [Full Text] [PDF]

				C. Operschall, L. Falivene, J.-P. Clozel, and S. Roux A new model of chronic cardiac ischemia in rabbits J Appl Physiol, April 1, 2000; 88(4): 1438 - 1445. [Abstract] [Full Text] [PDF]

				E. R. Schwarz, M. T. Speakman, M. Patterson, S. S. Hale, J. M. Isner, L. H. Kedes, and R. A. Kloner Evaluation of the effects of intramyocardial injection of DNA expressing vascular endothelial growth factor (VEGF) in a myocardial infarction model in the rat--angiogenesis and angioma formation J. Am. Coll. Cardiol., April 1, 2000; 35(5): 1323 - 1330. [Abstract] [Full Text] [PDF]

				J. D. Pearlman, R. J. Laham, and M. Simons Coronary Angiogenesis: Detection in Vivo with MR Imaging Sensitive to Collateral Neocirculation-Preliminary Study in Pigs Radiology, March 1, 2000; 214(3): 801 - 807. [Abstract] [Full Text]

				M. Fujita Heparin and angiogenic therapy Eur. Heart J., February 2, 2000; 21(4): 270 - 274. [PDF]

				M. Fleisch, M. Billinger, F. R. Eberli, A. R. Garachemani, B. Meier, and C. Seiler Physiologically Assessed Coronary Collateral Flow and Intracoronary Growth Factor Concentrations in Patients With 1- to 3-Vessel Coronary Artery Disease Circulation, November 9, 1999; 100(19): 1945 - 1950. [Abstract] [Full Text] [PDF]

				R. Konda, H. Sato, K. Sakai, M. Sato, S. Orikasa, and N. Kimura Expression of Platelet-Derived Endothelial Cell Growth Factor and its Potential Role in Up-Regulation of Angiogenesis in Scarred Kidneys Secondary to Urinary Tract Diseases Am. J. Pathol., November 1, 1999; 155(5): 1587 - 1597. [Abstract] [Full Text] [PDF]

				J. J. Walter and D. C. Sane Angiostatin Binds to Smooth Muscle Cells in the Coronary Artery and Inhibits Smooth Muscle Cell Proliferation and Migration In Vitro Arterioscler. Thromb. Vasc. Biol., September 1, 1999; 19(9): 2041 - 2048. [Abstract] [Full Text] [PDF]

				N. P J Brindle, M. J McCarthy, and P. R F Bell Angiogenic revascularisation in ischaemic disease BMJ, June 5, 1999; 318(7197): 1500 - 1501. [Full Text]

				T. D Henry Science, medicine, and the future: Therapeutic angiogenesis BMJ, June 5, 1999; 318(7197): 1536 - 1539. [Full Text]

				B Schwartzkopff and B.E Strauer Squeezing tubes: a case of remodeling and regulation: Coronary reserve in hypertensive heart disease Cardiovasc Res, October 1, 1998; 40(1): 4 - 8. [Full Text] [PDF]

				S. Senti, M. Fleisch, M. Billinger, B. Meier, and C. Seiler Long-term physical exercise and quantitatively assessed human coronary collateral circulation J. Am. Coll. Cardiol., July 1, 1998; 32(1): 49 - 56. [Abstract] [Full Text] [PDF]

				P. Carmeliet, L. Moons, and D. Collen Mouse models of angiogenesis, arterial stenosis, atherosclerosis and hemostasis Cardiovasc Res, July 1, 1998; 39(1): 8 - 33. [Abstract] [Full Text] [PDF]

				T. Kohmoto, C. M. DeRosa, N. Yamamoto, P. E. Fisher, P. Failey, C. R. Smith, and D. Burkhoff Evidence of Vascular Growth Associated With Laser Treatment of Normal Canine Myocardium Ann. Thorac. Surg., May 1, 1998; 65(5): 1360 - 1367. [Abstract] [Full Text] [PDF]

				C. A. Mack, S. R. Patel, E. A. Schwarz, P. Zanzonico, R. T. Hahn, A. Ilercil, R. B. Devereux, S. J. Goldsmith, T. F. Christian, T. A. Sanborn, et al. Biologic bypass with the use of adenovirus-mediated gene transfer of the complementary deoxyribonucleic acid for vascular endothelial growth factor 121 improves myocardial perfusion and function in the ischemic porcine heart J. Thorac. Cardiovasc. Surg., January 1, 1998; 115(1): 168 - 177. [Abstract] [Full Text] [PDF]

				J. Waltenberger Modulation of Growth Factor Action : Implications for the Treatment of Cardiovascular Diseases Circulation, December 2, 1997; 96(11): 4083 - 4094. [Abstract] [Full Text]

				G. Melillo, M. Scoccianti, I. Kovesdi, J. Safi Jr, T. Riccioni, and M. C Capogrossi Gene therapy for collateral vessel development Cardiovasc Res, September 1, 1997; 35(3): 480 - 489. [Abstract] [Full Text] [PDF]

				M. Ziche, A. Parenti, F. Ledda, P. Dell'Era, H. J. Granger, C. A. Maggi, and M. Presta Nitric Oxide Promotes Proliferation and Plasminogen Activator Production by Coronary Venular Endothelium Through Endogenous bFGF Circ. Res., June 19, 1997; 80(6): 845 - 852. [Abstract] [Full Text]

				M. S. Pepper Manipulating Angiogenesis: From Basic Science to the Bedside Arterioscler. Thromb. Vasc. Biol., April 1, 1997; 17(4): 605 - 619. [Abstract] [Full Text]

				B. Su, S. Mitra, H. Gregg, S. Flavahan, M. A. Chotani, K. R. Clark, P. J. Goldschmidt-Clermont, and N. A. Flavahan Redox Regulation of Vascular Smooth Muscle Cell Differentiation Circ. Res., July 6, 2001; 89(1): 39 - 46. [Abstract] [Full Text] [PDF]

				C. L. Buus, F. Pourageaud, G. E. Fazzi, G. Janssen, M. J. Mulvany, and J. G.R. De Mey Smooth Muscle Cell Changes During Flow-Related Remodeling of Rat Mesenteric Resistance Arteries Circ. Res., July 20, 2001; 89(2): 180 - 186. [Abstract] [Full Text] [PDF]

				H. Matsuo, S. Watanabe, T. Kadosaki, T. Yamaki, S. Tanaka, S. Miyata, T. Segawa, Y. Matsuno, M. Tomita, and H. Fujiwara Validation of Collateral Fractional Flow Reserve by Myocardial Perfusion Imaging Circulation, March 5, 2002; 105(9): 1060 - 1065. [Abstract] [Full Text] [PDF]

This Article Extract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Schaper, W. Articles by Ito, W. D. Search for Related Content PubMed PubMed Citation Articles by Schaper, W. Articles by Ito, W. D.