© 2000 American Heart Association, Inc.
Cellular Biology |
Contribution of Monocytes/Macrophages to Compensatory Neovascularization
The Drilling of Metalloelastase-Positive Tunnels in Ischemic Myocardium
From the Heart and Lung Institute and the Division of Cardiology, Department of Internal Medicine (N.I.M., P.J.G.-C.), and Neurobiotechnology Center (P.E.K, J.P.-T.), College of Medicine and Public Health, Ohio State University, Columbus, Ohio, and the Department of Pediatrics (S.D.S), Washington University School of Medicine, Barnes-Jewish Hospital, St. Louis, Mo.
Correspondence to Nicanor I. Moldovan, PhD, Heart and Lung Institute, Department of Internal Medicine, College of Medicine and Public Health, The Ohio State University, Medical Research Facility, Room 546, 420 W 12th Ave, Columbus, OH 43210. E-mail moldovan-1{at}medctr.osu.edu Pascal J. Goldschmidt-Clermont, MD, Duke University Medical Center, Box 3845, Durham, NC 27710.
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Abstract—In a transgenic model of ischemic cardiomyopathy in which monocytes are attracted to the myocardium by the targeted overexpression of monocyte chemoattractant protein-1 (MCP-1), we have observed the presence of endothelial NO synthase and platelet endothelial cell adhesion molecule-1–negative tunnels, occasionally containing blood-derived cells, that probe the cardiac tissue. Immunohistochemical data show that monocytes/macrophages (MCs/Mphs) drill tunnels using the broad-spectrum mouse macrophage metalloelastase. 5-Bromo-2'-deoxyuridine incorporation and neo-endothelial markers present in the microvasculature of MCP-1 mouse hearts suggest an active angiogenic process. Further studies will be required to establish that the MC-/Mph-drilled tunnels evolve to become capillaries, connected to the existing vessels and colonized by circulating endothelial cell progenitors. This possibility is supported by the availability of these cells, which is demonstrated by cell tagging with ß-galactosidase placed under an active endothelial Tie-2 promoter. This phenomenon might represent another mechanism, in addition to the secretion of the angiogenic factors, by which MCs/MPhs may participate in the elaboration of new blood vessels in adult tissues.
Key Words: monocytes • metalloelastase • angiogenesis • ischemic heart disease
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Angiogenesis refers to a process in which new capillaries extend from existing vessels to carry blood to ischemic tissues.1 Proliferation and migration of endothelial cells (ECs) are instrumental to the genesis of sprouting vessels.2 Under the control of multiple factors, ECs are induced to form capillary tubes that are connected to existing vessels and expand distally to tissues that are in need of additional blood supply. For example, the growth of tumors is exquisitely dependent on the supply of blood, which requires angiogenesis within the cancerous tissue.3 In turn, the progression of the angiogenic process is tightly controlled by the production of both angiogenic factors, such as basic fibroblast growth factor4 or vascular endothelial growth factor,5 and angiostatic factors, such as tissue inhibitors of metalloproteinases,6 angiostatin,7 or endostatin.8 A steady-state balance is established between agonistic and antagonistic factors, which defines the angiogenic activity, and consequently, the alteration of this balance may have an impact on ischemic tissue recovery or on tumor growth.9
However, it has recently been shown that some rapidly growing tumors may rely on a different mechanism of blood supply, called "vascular mimicry," which consists in formation of periodic acid-Schiff (PAS)–positive, endothelium-free "tunnels" apparently drilled within the tumoral matrix by the cancer cells themselves.10 This endothelial disguise may go so far that the epithelial tumor cell line T24/83 was for a long time mistaken for an EC line, ECV 304.11
In this study we present data that suggest a similar genesis of alternative microcirculation formation occurring in the ischemic myocardium, in which the native capillary network collapsed as a consequence of transgenically induced upstream occlusion due to thrombosis or other pathological processes and in which monocytes/macrophages (MCs/Mphs) are attracted by chemotaxis. In the myocardium, a dense matrix of extracellular proteins connects the cardiomyocytes (CMs) to form a compact tissue that is capable of generating force and sustaining substantial transmural pressures during systole. Chronic ischemia of the myocardium resulting from epicardial coronary atherosclerosis is associated, in a subset of patients, with the enlargement of existing arterioles (arteriogenesis)12 and the sprouting of new capillaries (angiogenesis, in its "classical" meaning)1 3 to generate a network of collateral vessels. The presence of such collaterals can markedly reduce damage to the myocardium that is produced by acute or chronic ischemia.
In such a setting, and because of the unique properties of the myocardial tissue, researchers had anticipated that the process of formation of new blood vessels might have particular characteristics, including the contribution of MCs/MPhs,12 13 and induction of adult-type vasculogenesis based on circulating precursor ECs.14 Data presented here suggest that in this instance, in addition to their secretion of endothelial growth factors,15 the inflammatory cells may contribute to a compensatory microcirculation with their ability to "tunnelize" the ischemic regions. The conduits thus created can facilitate the access of other blood components, setting up a tubular network prone to the re-establishment of a collateral microvascular system.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Animals
The construction and characterization of the transgenic mouse model expressing monocyte chemoattractant protein-1 (MCP-1) selectively in the heart, under the myosin heavy chain promoter
, has been
described previously.16 Homozygous (4- to 6-month-old) and
heterozygous (8- to 10-month-old) MCP-1 mice or LacZ-Tie-2–expressing
transgenic mice (The Jackson Laboratory) and age-matched wild type
controls were euthanized with CO2. The hearts
were collected, either cryofixed or fixed in buffered 10% formalin or
in methanol, and embedded in paraffin for sectioning and for further
histological and immunohistochemical staining. All
protocols were approved by the Ohio State University Institutional
Animal Care and Use Committee.
Histology and Ultrastructural Analysis
Paraffin sections were stained with hematoxylin and eosin (HE),
Weigert’s elastic van Gieson (EVG), or PAS reagent with hematoxylin
counterstaining. For electron microscopy, the tissues were fixed with
3% glutaraldehyde in 0.1 mol/L phosphate buffer
supplemented with 10 mmol/L sucrose for 3 hours, postfixed in 1%
osmium tetraoxide, dehydrated in graded ethanol, and embedded in Spurr
resin. Ultramicrotome sections were counterstained with 2% uranyl
acetate and Reynolds’ lead citrate and examined with a Phillips CM-12
electron microscope operated at 60 kV.
Immunohistochemistry
Immunostaining was done on paraffin sections by
using the following antibodies: anti–smooth muscle -actin (clone
1A4) from Sigma; anti-Thy-1, anti–platelet endothelial cell adhesion
molecule-1 (PECAM-1), anti–endothelial NO
synthase (eNOS), and anti-Mac-3 from PharMingen; and rabbit anti-mouse
MC/Mph metalloelastase (MME), which was prepared as
described.17 The detection system for these antibodies
comprised Vectastain ABC-peroxidase and avidin/biotin blocking kits
from Vector Laboratories. The sections were counterstained with
hematoxylin. For the assessment of cell proliferation, mice were
implanted with osmotic minipumps (Alza Corp) releasing
5-bromo-2'-deoxyuridine (BrdU, Sigma) at a rate of 25 mg/kg per day for
10 days. Paraffin sections obtained from the labeled hearts were
immunostained for BrdU incorporation using a commercial kit
(Zymed Laboratories).
Exposure of MCP-1 Hearts to Circulating, Labeled
Endothelial Progenitor Cells
To perfuse chronically the MC-tunneled tissues with mouse blood
containing labeled progenitor ECs,18 the MCP-1 hearts were
transplanted heterotopically19 to syngeneic
recipients transgenically modified to express ß-galactosidase under
the control of the endothelial marker
Tie-2.20 The data presented were obtained from a
nonrejected (beating) MCP-1 heart, which was harvested 5 days after
transplantation, included in OCT, cryosectioned, and stained for
ß-galactosidase activity.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
MME-Lined Tunnels Found in MCP-1 Hearts
In a previous report,16 we demonstrated the targeted expression of MCP-1 in the myocardium of transgenic mice under the control of the myosin heavy chain promoter. We have also provided data indicating that expression of the MCP-1 gene under the control of this cardiac-selective promoter induced the progressive accumulation of MCs within myocardium. The MCP-1 secretion and the subsequent MC infiltration remained asymptomatic during the early life of most of the animals. However, in the homozygous mice, the targeted expression of MCP-1 eventually produced the deterioration of cardiac function, with myocardial enlargement, heart failure, and premature death (N.I. Moldovan et al, unpublished results, 1998). The detailed pathogenesis of this cardiomyopathy is currently under investigation.
With the advancement of the cardiomyopathic process, we
observed on microscopic sections a multitude of tunnels within the
myocardium of MCP-1 mice, which had not been recognized in
our previous study of this model (Figures 1
, 3, and 4). Therefore, we
addressed the hypothesis that MCs/Mphs might be using potent
metalloproteinases to infiltrate the myocardial tissue. The
broad-spectrum mouse metalloelastase MME21 was
immunodetected as being associated with MCs/Mphs and lining empty
cylindrical spaces (tunnels) found in longitudinal and transversal
sections of MCP-1 myocardium (Figures 1A and 1C through 1G). A particular feature, present in 2 of
6 examined specimens, was a higher intensity of the
immunostaining in the subendocardial
myocardium (Figure 1A), suggesting a likely,
although indirect, association between tunneling and ischemia
in this model. MME positivity was not present in the endocardium of
control, wild-type littermates (Figure 1B).
|
|
|
MME is a proteinase specific to MCs/Mphs21 and,
together with the Mac-3 antigen, was used here to confirm the MC/Mph
phenotype of tunnel-forming, infiltrating mononuclear cells
(Figure 1H
). MME staining was also present in the avascular
tissue of cardiac valves (Figure 1F) but was absent within
native microvessels (Figure 1G). These observations suggest that
the tunnels and the capillaries are distinct entities.
The concurrent finding of extravascular structures staining for MME and
of MME-positive MCs/Mphs (Figures 1C, 1E, and 4A)
within these tunnels strongly suggest, although do not definitively
prove, the implication of MCs/Mphs in the process of tunnel formation.
Indeed, MCs/Mphs displaying migratory, elongated morphology could be
detected within these tunnels (Figures 1E and 1H).
Ischemia of the MCP-1 Hearts
Cross sections of failing MCP-1 mouse hearts revealed both intact
epicardial coronary vessels (Figure 2B) and vessels affected by an occlusive
vasculopathy (Figure 2A), with destruction of the elastic lamina
and thrombotic complications. Moreover, many small arterioles were
occluded, either by cellular (Figure 2C) or thrombotic (not
shown) elements.
|
Downstream from the obstructed and thrombosed coronary arteries
within the hearts of MCP-1 mice, signs of ischemic
cardiomyopathic changes could be observed. Although the
recruitment of MCs/Mphs to the myocardium per se could have
contributed to the myocardial damage, we have accumulated evidence that
loss of functional blood vessels may have also contributed to the
cardiomyopathic process. We detected typical
contraction bands (Figure 2D), whereas ultrastructural
analysis of MCP-1 hearts by electron microscopy demonstrated
swollen mitochondria with electron-dense deposits (Figure 2E),
myofibril breakdown, and Z-band disorganization within CMs (Figure 2F). Myocytolysis with extensive CM loss was detected as well
(Figures 1H, 3G, and 4F). These changes
were consistent with the expected findings for an
ischemic cardiomyopathy
model.22 23
Blood Elements Are Found in Tunnels, Which May Contribute to
Neovascularization
A detailed histological examination of MCP-1
hearts confirmed the presence of a network of tunnels of fairly uniform
diameter, usually devoid of ECs (Figure 3A). PAS staining of MCP-1 hearts
revealed PAS-positive structures of which the distribution was similar
to that of MME-positive tunnels (Figure 3C), as well as
occasional PAS-positive mononuclear cells (Figure 3C, arrowhead). Well-organized tunnel-like structures (PAS- and
MME-positive), the detection of which is possibly facilitated by an
increased incidence of edema, were found exclusively in
MCP-1–expressing hearts and were largely absent from the hearts of
nontransgenic littermates (Figures 3B and 3D), ruling out
the possibility of processing artifacts.
The possible existence of 2 distinct microvascular structures in MCP-1
hearts was also suggested by immunostaining for 2
endothelial markers, eNOS and PECAM-1.
Erythrocyte-filled, eNOS-negative tunnels were detected in MCP-1 hearts
along with eNOS-positive microvessels (Figure 3E). In the
wild-type control mice, all erythrocytes were confined to a
high-density network of eNOS-positive capillaries (Figure 3F).
This result was confirmed by the distribution of PECAM-1
immunoreactivity, which was found to be almost absent in the tunnel
containing MCP-1 hearts (Figure 3G), whereas PECAM-1 was
present in the wild-type controls at comparable levels with eNOS
immunostaining (Figure 3H).
Some nonendothelialized tunnels contained blood
components, such as MCs (Figures 1E and 4A) and
erythrocytes (Figures 3A, 3E, and 4C), whereas
other tunnels were apparently colonized by EC-like cells (Figures 4A, 4B, and 4E). This
finding is consistent with, although it does not prove, a
process in which MC-/Mph-drilled tunnels can evolve to become
neocapillaries if connected by a still-unknown mechanism to the
microcirculatory system.
To collect additional support for this hypothesis, we stained
paraffin sections from MCP-1 hearts with an antibody to Thy-1, a marker
of hematopoietic stem cells, which is believed to be expressed also on
ECs during adult neovascularization.24 Clusters of small
vessels and incidental mononuclear cells were positive for Thy-1
staining (Figure 4F). In other microscopic fields, we found a
patchy staining for Thy-1 within the contour of a single capillary
(N.I. Moldovan, unpublished data, 2000).
An active angiogenic process was also indicated by the finding that
many cells with EC morphology lining the tunnels displayed signs of DNA
synthesis as assessed by BrdU incorporation (Figure 4B). The
endothelial nature of the cells found within the
tunnels was further supported by ultrastructural analysis,
which revealed the presence of large vacuoles (Figure 4E),
presumably the precursors of capillary lumens, as shown for sprouting
ECs.25
Moreover, when transplanted in recipients transgenically expressing
ß-galactosidase under an active endothelium-specific
Tie-2 promoter (Figure 4D), MCP-1 hearts displayed a sparse
infiltration with mononuclear, ß-galactosidase–positive, presumably
precursor ECs, both in capillaries and in tunnel-like structures
(Figure 4C).
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
In this study, we describe a network of MME-positive tubular structures (tunnels) penetrating the extracellular matrix and associated with the presence of MCs/Mphs in the myocardium of mice topically expressing MCP-1. As will be detailed below, the definition of a tunnel is not limited to a tubular "empty space," but a tunnel is also characterized by the distribution of the nuclei of colonizing cells, MME immunostaining, and endothelial markers.
We have accumulated the following evidence that the infiltrating mononuclear cells produced these tunnels using the proteolytic activity localized at their surface: (1) MME-positive cells were found in tunnels, (2) the cross-sectional size of tunnels is in the range of diameters of mononuclear cells, (3) regions where MCs/Mphs are present display increased MME immunostaining, and (4) the finding of empty MME-positive tunnels suggests that they are produced by migrating MCs/Mphs.
MME, the mouse homologue of human matrix metalloprotease 12, is a broad-spectrum metalloprotease specifically produced by mononuclear phagocytic cells.21 Its expression correlates with MC/Mph activation status.26 MME is differentially expressed and clustered around vascular structures during experimental angiogenesis in the mouse.27 MME was shown to be necessary for the penetration of basement membranes by MCs/Mphs in vivo and in vitro and for degradation of extracellular matrix proteins.28 Although direct evidence is lacking, correlative data suggest that tissular activity of metalloelastases is downregulated in some instances by tissue inhibitors of metalloproteinases29 and possibly stimulated by urokinase-type plasminogen activator.30 Both of these regulators are known to be modulated by ischemic conditions.31 32
Therefore, the preferential immunostaining for MME found within the subendocardial region of MCP-1 hearts supports the possibility of an ischemia-driven activation of MCs/MPhs and, consequently, an MME-based proteolytic activity. In view of the report that MME production is not affected by MCP-1 levels,33 our finding that MME activity and MC-/MPh-based tunneling are associated with the advanced stages of ischemic cardiomyopathy in this model might suggest that ischemia itself, or other factors related to ischemia, may contribute to the observed tunneling, although a more direct role for MCP-1 in this process cannot be ruled out.
Activation of MCs/MPhs increases their ability to invade the extracellular matrices in vitro as well, producing lasting tunnels similar to those described here.34 Moreover, phorbol 12-myristate 13-acetate, an MC/MPh activator responsible for this effect, is also known as an inducer of MME.26
Previous studies suggested that MME might be anti-angiogenic, because of its ability to form angiostatin from plasminogen in vitro35 and to form endostatin from collagen XVIII.36 If this were the case, one would expect that the inhibition of MME would stimulate angiogenesis. In fact, MME displays an exquisite sensitivity to downregulation by dexamethasone,26 27 but contrary to expectations, this effect actually parallels a reduction, not the stimulation of angiogenic process in a murine wound-healing model in vivo.27 Moreover, the mere presence of an MME antigen lining the tunnels, presumably representing MME molecules or fragments thereof (supposedly shed during MC/Mph migration), does not necessarily imply that the enzyme is still active. Actually, the limited and fairly uniform diameter of tunnels argues that MME activity is tightly regulated by local inhibitors.
In longitudinal, oblique, and transversal cross sections (as required in a critique of the tumor-associated PAS-positive "channels,"37 which were recently described as a form of "vascular mimicry"10 ), we found PAS-staining material lining some of the endothelium-free tunnels, which might contribute to the retention and possibly to the differentiation of circulating EC progenitor cells.
In tunnels found in MCP-1 hearts, we could detect blood products such as erythrocytes and EC-like (ie, attached to tunnels’ walls) cells. This observation raises the intriguing possibility that some MC-/Mph-produced tunnels, if connected to a blood supply, can be colonized in a later stage by circulating precursor ECs displaying heightened mitotic activity.18 We were able to confirm the availability of circulating precursor ECs by Tie-2 cell tagging of the infiltrate of the MCP-1 myocardium and by the presence of immature ECs, by electron microscopy.
We consider it improbable that the infiltrating, Tie-2–driven, ß-galactosidase–positive ECs could have migrated within the transplanted myocardium as a result of a sprouting process, given the distance from the sutures between the recipient’s ß-galactosidase–positive endothelia and the actual places where we observed the tagged cells in the transplanted heart, as well as their individualized, single-cell localization. Furthermore, it is known that the re-endothelialization of grafts proceeds through the "fallout" of blood-derived, proliferating, BrdU-positive endothelial precursors.38 However, we do not rule out that blue cells originated from the recipient vessels and renested in the graft capillaries.
Discontinuity ("spottiness") of the covering with ECs along a given
tunnel, and of the labeling for markers of neoangiogenesis within and
among microvessels (Figure 4), makes the sprouting an unlikely
mechanism of re-endothelialization in our model of
ischemic heart failure. One would expect ECs occurring by
sprouting to be in contact with one another (contiguous) and of similar
phenotype. New endothelial covering of former
de-endothelialized capillaries may be ruled out as well
on the basis of the MME positivity of the tunnels. Therefore, our
findings can be better interpreted within the new paradigm of adult
vasculogenesis14 18 on the basis of the dissemination of
circulating precursor ECs. In this respect, the data reported in this
study may contribute to understanding the mechanism of engrafting of
circulating endothelial precursors within the
ischemic tissue.
One may consider the presence of erythrocytes within endothelium-free tunnels in MCP-1 hearts as a manifestation of the leakiness of defective or immature capillaries. However, to our knowledge this type of leakiness was convincingly demonstrated mostly in the microcirculation of some tumors.39 Otherwise, what is generally considered "leakiness" of new capillaries refers mostly to an increased molecular permeability to solutes, which might be the effect of vascular endothelial growth factor (also known as the "vascular permeability factor") on the transcellular diffusion of macromolecules rather than creation of large interendothelial junctional defects.40 41
The limited amount of blood we found in tunnels may be explained either by the variable extension of their connection to the bona fide blood conduits or by the postmortem washing out of blood. However, in an in vitro model, we have been able to demonstrate the formation of tunnels by MCs/Mphs in extracellular matrices, the stimulating effect of MCP-1 on this process, and the ability of these tunnels to be filled by blood-derived erythrocytes (N.I. Moldovan, unpublished data, 2000).
In conclusion, with the availability of a transgenic model in which the development of a dilated ischemic cardiomyopathy can be reliably reproduced by targeted expression of MCP-1 in the myocardium, we made a series of observations that are shedding light on a possible novel mechanism of neovasculogenesis as it takes place in the ischemic myocardium and on the role of MCs/Mphs in this process, indicating new strategic targets for therapeutic angiogenesis.
|
Acknowledgments |
|---|
This work was supported by NIH Grants GM53236 and HL52315 (to P.J.G.-C.) and HL48916 (to P.E.K); by the American Heart Association (Established Investigator award to P.J.G.-C.); by an award from the American Heart Association, Ohio Valley Affiliate (to N.I.M.); and by the Scleroderma Research Foundation.
Received June 6, 2000; revision received July 11, 2000; accepted July 11, 2000.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
- Folkman J, D’Amore PA. Blood vessel formation: what is its molecular basis? Cell. 1996;87:1153–1155.[Medline] [Order article via Infotrieve]
- Klagsburn M, D’Amore PA. Regulators of angiogenesis. Annu Rev Physiol. 1991;53:217–239.[Medline] [Order article via Infotrieve]
- Folkman J. Inhibition of angiogenesis. Semin Cancer Biol. 1992;3:65–71.[Medline] [Order article via Infotrieve]
- Isner JM. The role of angiogenic cytokines in cardiovascular disease. Clin Immunol Immunopathol. 1996;80:S82–S91.[Medline] [Order article via Infotrieve]
- Ferrara N. Vascular endothelial growth factor: molecular and biological aspects. Curr Top Microbiol Immunol. 1999;237:1–30.[Medline] [Order article via Infotrieve]
-
Carmeliet P, Collen D. Molecular analysis of
blood vessel formation and disease. Am J Physiol. 1997;273:H2091–H2104.
[Abstract/Free Full Text] - O’Reilly MS. Angiostatin: an endogenous inhibitor of angiogenesis and of tumor growth. EXS. 1997;79:273–294.[Medline] [Order article via Infotrieve]
- Zetter BR. Angiogenesis and tumor metastasis. Annu Rev Med. 1998;49:407–424.[Medline] [Order article via Infotrieve]
- Folkman J. New perspectives in clinical oncology from angiogenesis research. Eur J Cancer. 1996;32A:2534–2539.
-
Maniotis AJ, Folberg R, Hess A, Seftor EA, Gardner LM,
Pe’er J, Trent JM, Meltzer PS, Hendrix MJ. Vascular tunnel formation
by human melanoma cells in vivo and in vitro: vasculogenic mimicry.
Am J Pathol. 1999;155:739–752.
[Abstract/Free Full Text] - Brown J, Reading SJ, Jones S, Fitchett CJ, Howl J, Martin A, Longland CL, Michelangeli F, Dubrova YE, Brown CA. Critical evaluation of ECV304 as a human endothelial cell model defined by genetic analysis and functional responses: a comparison with the human bladder cancer derived epithelial cell line T24/83. Lab Invest. 2000;80:37–45.[Medline] [Order article via Infotrieve]
-
Schaper W, Ito WD. Molecular mechanisms of
coronary collateral vessel growth. Circ Res. 1996;79:911–919.
[Free Full Text] - Schaper W. Control of coronary angiogenesis. Eur Heart J. 1995;16(suppl C):66–68.
- Isner JM, Takayuki A. Therapeutic angiogenesis. Front Biosci. 1998;5:e49–e69.
-
Hojo Y, Ikeda U, Zhu Y, Okada M, Ueno S, Arakawa
H, Fujikawa H, Katsuki T, Shimada K. Expression of vascular
endothelial growth factor in patients with acute
myocardial infarction. J Am Coll Cardiol. 2000;35:968–973.
[Abstract/Free Full Text] - Kolattukudy PE, Quach T, Bergese S, Breckenridge S, Hensley J, Altschuld R, Gordillo G, Klenotic S, Orosz C, Parker-Thornburg J. Myocarditis induced by targeted expression of the MCP-1 gene in murine cardiac muscle. Am J Pathol. 1998;152:101–111.[Abstract]
-
Shipley JM, Wesselschmidt RL, Kobayashi DK, Ley TJ,
Shapiro SD. Metalloelastase is required for
macrophage-mediated proteolysis and matrix invasion in mice.
Proc Natl Acad Sci U S A. 1996;93:3942–3946.
[Abstract/Free Full Text] -
Asahara T, Masuda H, Takahashi T, Kalka C, Pastore C,
Silver M, Kearne M, Magner M, Isner JM. Bone marrow origin of
endothelial progenitor cells responsible for postnatal
vasculogenesis in physiological and pathological
neovascularization. Circ Res. 1999;85:221–228.
[Abstract/Free Full Text] - Ardehali A, Billingsley A, Laks H, Drinkwater DC Jr, Sorensen TJ, Drake TA Experimental cardiac allograft vasculopathy in mice. J Heart Lung Transplant. 1993;12:730–735.[Medline] [Order article via Infotrieve]
-
Schlaeger TM, Bartunkova S, Lawitts JA, Teichmann G,
Risau W, Deutsch U, Sato TN. Uniform
vascular-endothelial-cell-specific gene expression in
both embryonic and adult transgenic mice. Proc Natl Acad Sci
U S A. 1997;94:3058–3063.
[Abstract/Free Full Text] - Shapiro SD. Diverse roles of macrophage matrix metalloproteinases in tissue destruction and tumor growth. Thromb Haemost. 1999;82:846–849.[Medline] [Order article via Infotrieve]
- Jennings RB, Sommers HM, Herdson PB, Kattenbach JP. Ischemic injury of the myocardium. Ann N Y Acad Sci. 1969;156:61–78.[Medline] [Order article via Infotrieve]
-
Golenhofen N, Ness W, Koob R, Htun P, Schaper W,
Drenckhahn D. Ischemia-induced phosphorylation
and translocation of stress protein B-crystallin to Z lines of
myocardium. Am J Physiol. 1998;274:H1457–H1464.
[Abstract/Free Full Text] -
Lee WS, Jain MK, Arkonac BM, Zhang D, Shaw SY, Kashiki
S, Maemura K, Lee SL, Hollenberg NK, Lee ME, Haber E. Thy-1, a novel
marker for angiogenesis upregulated by inflammatory cytokines.
Circ Res. 1998;82:845–851.
[Abstract/Free Full Text] - Folkman J, Haudenschild C. Angiogenesis in vitro. Nature. 1980;288:551–556.[Medline] [Order article via Infotrieve]
- Monet-Kuntz C, Cuvelier A, Sarafan N, Martin JP. Metalloelastase expression in a mouse macrophage cell line—regulation by 4-ß-phorbol 12-myristate 13-acetate, lipopolysaccharide and dexamethasone. Eur J Biochem. 1997;247:588–595.[Medline] [Order article via Infotrieve]
- Madlener M, Parks WC, Werner S. Matrix metalloproteinases (MMPs) and their physiological inhibitors (TIMPs) are differentially expressed during excisional skin wound repair. Exp Cell Res. 1998;242:201–210.[Medline] [Order article via Infotrieve]
- Vaalamo M, Kariniemi AL, Shapiro SD, Saarialho-Kere U. Enhanced expression of human metalloelastase (MMP-12) in cutaneous granulomas and macrophage migration. J Invest Dermatol. 1999;112:499–505.[Medline] [Order article via Infotrieve]
-
Forough R, Lea H, Starcher B, Allaire E, Clowes M,
Hasenstab D, Clowes AW. Metalloproteinase blockade by local
overexpression of TIMP-1 increases elastin accumulation in rat carotid
artery intima. Arterioscler Thromb Vasc Biol. 1998;18:803–807.
[Abstract/Free Full Text] - Heymans S, Luttun A, Nuyens D, Theilmeier G, Creemers E, Moons L, Dyspersin GD, Cleutjens JP, Shipley M, Angellilo A, Levi M, Nube O, Baker A, Keshet E, Lupu F, Herbert JM, Smits JF, Shapiro SD, Baes M, Borgers M, Collen D, Daemen MJ, Carmeliet P. Inhibition of plasminogen activators or matrix metalloproteinases prevents cardiac rupture but impairs therapeutic angiogenesis and causes cardiac failure. Nat Med. 1999;5:1135–1142.[Medline] [Order article via Infotrieve]
- Tyagi SC, Kumar SG, Haas SJ, Reddy HK, Voelker DJ, Hayden MR, Demmy TL, Schmaltz RA, Curtis JJ. Post-transcriptional regulation of extracellular matrix metalloproteinase in human heart end-stage failure secondary to ischemic cardiomyopathy. J Mol Cell Cardiol. 1996;28:1415–1428.[Medline] [Order article via Infotrieve]
- Ahn MY, Zhang ZG, Tsang W, Chopp M. Endogenous plasminogen activator expression after embolic focal cerebral ischemia in mice. Brain Res. 1999;837:169–176.[Medline] [Order article via Infotrieve]
- Kumar R, Dong Z, Fidler IJ. Differential regulation of metalloelastase activity in murine peritoneal macrophages by granulocyte-macrophage colony-stimulating factor and macrophage colony-stimulating factor. J Immunol. 1996;157:5104–5111.[Abstract]
- Castellucci M, Montesano R. Phorbol ester stimulates macrophage invasion of fibrin matrices. Anat Rec. 1988;220:1–10.[Medline] [Order article via Infotrieve]
-
Cornelius LA, Nehring LC, Harding E, Bolanowski
M, Welgus HG, Kobayashi DK, Pierce RA, Shapiro SD. Matrix
metalloproteinases generate angiostatin: effects on neovascularization.
J Immunol. 1998;161:6845–6852.
[Abstract/Free Full Text] -
Wen W, Moses MA, Wiederschain D, Arbiser JL,
Folkman J. The generation of endostatin is mediated by elastase.
Cancer Res. 1999;59:6052–6056.
[Abstract/Free Full Text] -
McDonald DM, Munn L, Jain RK. Vasculogenic
mimicry: how convincing, how novel, and how significant? Am
J Pathol. 2000;156:383–388.
[Free Full Text] - Onuki Y, Kouchi Y, Yoshida H, Wu MH, Shi Q, Wechezak AR, Coan D, Sauvage LR. Early flow surface endothelialization before microvessel ingrowth in accelerated graft healing, with BrdU identification of cellular proliferation. Ann Vasc Surg. 1998;12:207–215.[Medline] [Order article via Infotrieve]
-
Hashizume H, Baluk P, Morikawa S, McLean JW, Thurston
G, Roberge S, Jain RK, McDonald DM. Openings between defective
endothelial cells explain tumor vessel leakiness.
Am J Pathol. 2000;156:1363–1380.
[Abstract/Free Full Text] - Dvorak HF, Nagy JA, Feng D, Brown LF, Dvorak AM. Vascular permeability factor/vascular endothelial growth factor and the significance of microvascular hyperpermeability in angiogenesis. Curr Top Microbiol Immunol. 1999;237:97–132.[Medline] [Order article via Infotrieve]
- Feng D, Nagy JA, Dvorak AM, Dvorak HF. Different pathways of macromolecule extravasation from hyperpermeable tumor vessels. Microvasc Res. 2000;59:24–37.[Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  J. Niu, A. Azfer, O. Zhelyabovska, S. Fatma, and P. E. Kolattukudy Monocyte Chemotactic Protein (MCP)-1 Promotes Angiogenesis via a Novel Transcription Factor, MCP-1-induced Protein (MCPIP) J. Biol. Chem., May 23, 2008; 283(21): 14542 - 14551. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. L. Duvall, D. Weiss, S. T. Robinson, F. M.F. Alameddine, R. E. Guldberg, and W. R. Taylor The Role of Osteopontin in Recovery from Hind Limb Ischemia Arterioscler. Thromb. Vasc. Biol., February 1, 2008; 28(2): 290 - 295. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C Stumpf, C Lehner, D Raaz, A Yilmaz, T Anger, W G Daniel, and C D Garlichs Platelets contribute to enhanced MCP-1 levels in patients with chronic heart failure Heart, January 1, 2008; 94(1): 65 - 69. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Morimoto, M. Takahashi, Y. Shiba, A. Izawa, H. Ise, M. Hongo, K. Hatake, K. Motoyoshi, and U. Ikeda Bone Marrow-Derived CXCR4+ Cells Mobilized by Macrophage Colony-Stimulating Factor Participate in the Reduction of Infarct Area and Improvement of Cardiac Remodeling after Myocardial Infarction in Mice Am. J. Pathol., September 1, 2007; 171(3): 755 - 766. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. van Amerongen, M. C. Harmsen, N. van Rooijen, A. H. Petersen, and M. J.A. van Luyn Macrophage Depletion Impairs Wound Healing and Increases Left Ventricular Remodeling after Myocardial Injury in Mice Am. J. Pathol., March 1, 2007; 170(3): 818 - 829. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Nishiwaki, M. Yoshida, H. Iwaguro, H. Masuda, N. Nitta, T. Asahara, and M. Isobe Endothelial E-Selectin Potentiates Neovascularization via Endothelial Progenitor Cell-Dependent and -Independent Mechanisms Arterioscler. Thromb. Vasc. Biol., March 1, 2007; 27(3): 512 - 518. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Niu, A. Azfer, L. M. Rogers, X. Wang, and P. E. Kolattukudy Cardioprotective effects of cerium oxide nanoparticles in a transgenic murine model of cardiomyopathy Cardiovasc Res, February 1, 2007; 73(3): 549 - 559. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Li, E. Calvo, M. Cool, P. Chrobak, D. G. Kay, and P. Jolicoeur Overexpression of Notch1 Ectodomain in Myeloid Cells Induces Vascular Malformations through a Paracrine Pathway Am. J. Pathol., January 1, 2007; 170(1): 399 - 415. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. C. Schatteman, M. Dunnwald, and C. Jiao Biology of bone marrow-derived endothelial cell precursors Am J Physiol Heart Circ Physiol, January 1, 2007; 292(1): H1 - H18. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A Charest, A Pepin, R Shetty, C Cote, P Voisine, F Dagenais, P Pibarot, and P Mathieu Distribution of SPARC during neovascularisation of degenerative aortic stenosis Heart, December 1, 2006; 92(12): 1844 - 1849. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Morimoto, M. Takahashi, A. Izawa, H. Ise, M. Hongo, P. E. Kolattukudy, and U. Ikeda Cardiac Overexpression of Monocyte Chemoattractant Protein-1 in Transgenic Mice Prevents Cardiac Dysfunction and Remodeling After Myocardial Infarction Circ. Res., October 13, 2006; 99(8): 891 - 899. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Azfer, J. Niu, L. M. Rogers, F. M. Adamski, and P. E. Kolattukudy Activation of endoplasmic reticulum stress response during the development of ischemic heart disease Am J Physiol Heart Circ Physiol, September 1, 2006; 291(3): H1411 - H1420. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Rutkowski, K. C. Boardman, and M. A. Swartz Characterization of lymphangiogenesis in a model of adult skin regeneration Am J Physiol Heart Circ Physiol, September 1, 2006; 291(3): H1402 - H1410. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W.-H. Zimmermann, M. Didie, S. Doker, I. Melnychenko, H. Naito, C. Rogge, M. Tiburcy, and T. Eschenhagen Heart muscle engineering: An update on cardiac muscle replacement therapy Cardiovasc Res, August 1, 2006; 71(3): 419 - 429. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Leor, L. Rozen, A. Zuloff-Shani, M. S. Feinberg, Y. Amsalem, I. M. Barbash, E. Kachel, R. Holbova, Y. Mardor, D. Daniels, et al. Ex Vivo Activated Human Macrophages Improve Healing, Remodeling, and Function of the Infarcted Heart Circulation, July 4, 2006; 114(1_suppl): I-94 - I-100. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Niu, A. Azfer, and P. E. Kolattukudy Monocyte-specific Bcl-2 expression attenuates inflammation and heart failure in monocyte chemoattractant protein-1 (MCP-1)-induced cardiomyopathy Cardiovasc Res, July 1, 2006; 71(1): 139 - 148. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Awad, E. I. Dedkov, C. Jiao, S. Bloomer, R. J. Tomanek, and G. C. Schatteman Differential Healing Activities of CD34+ and CD14+ Endothelial Cell Progenitors Arterioscler. Thromb. Vasc. Biol., April 1, 2006; 26(4): 758 - 764. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Anghelina, P. Krishnan, L. Moldovan, and N. I. Moldovan Monocytes/Macrophages Cooperate with Progenitor Cells during Neovascularization and Tissue Repair: Conversion of Cell Columns into Fibrovascular Bundles Am. J. Pathol., February 1, 2006; 168(2): 529 - 541. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Glod, D. Kobiler, M. Noel, R. Koneru, S. Lehrer, D. Medina, D. Maric, and H. A. Fine Monocytes form a vascular barrier and participate in vessel repair after brain injury Blood, February 1, 2006; 107(3): 940 - 946. |