© 2001 American Heart Association, Inc.
Editorials |
The Putative Convergent and Divergent Natures of Angiogenesis and Arteriogenesis
From the Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, Maine and the Center for Biophysical Sciences, University of Maine, Orono, Maine.
Correspondence to Thomas Maciag, Center for Molecular Medicine, Maine Medical Center Research Institute, 81 Research Dr, Scarborough, ME 04074. E-mail maciat{at}mmc.org
Key Words: fibroblast growth factor • hypoxia • monocyte chemotactic protein-1 • stress • vascular endothelial growth factor
The postnatal function of blood vessels is determined by the physiology of individual tissues and organs as well as the size and mass of an individual species, and a corollary to this premise is the suggestion that not all blood vessels are created equal. Postnatally, new blood vessel growth occurs either by angiogenesis or arteriogenesis, and thus, it is anticipated that the mechanisms responsible for these processes will exhibit convergent and divergent features.1 Because angiogenesis involves the coordinated migration, proliferation, and differentiation of endothelial cells (ECs) and pericytes from existing vascular beds and arteriogenesis, the growth of muscular arteries, requires similar events regulated by ECs and smooth muscle cells (SMCs) from preexisting arteries, it is anticipated that these cells will have evolved divergent mechanisms responsible for their postnatal development and growth.2,3 Indeed, a recent study by Hershey et al4 examined the relationship between angiogenesis and arteriogenesis in the development of functional collateral blood vessels in the rabbit ischemic hind limb model and observed that although capillary sprouting via angiogenesis occurred as an early response to tissue ischemia, improved collateral blood flow occurred only as a late response when arteriogenesis could be demonstrated using angiographic methods. These data suggest that a temporal relationship may exist between angiogenesis and arteriogenesis in which the angiogenic component precedes the arteriogenic component in the formation of a collateral vasculature visualized by angiographic methods.
The angiogenesis factor, VEGF, is well described as a rapidly induced hypoxia-response gene.5 If angiogenesis and arteriogenesis were not temporally related, it is likely that the mechanisms responsible for the angiogenic and arteriogenic responses may both be due to the function of enhanced VEGF expression and VEGF receptor–mediated signaling because the expression of VEGF is an immediate and rapid event. However, a direct role for VEGF in the angiogenic component of arteriogenesis has been quite controversial.6–9 In this issue of Circulation Research, Deindl et al10 provide direct experimental evidence that neither endogenous nor exogenous VEGF contribute directly to arteriogenesis. These investigators report that the levels of endogenous VEGF and its high-affinity receptors, VEGFR1 and VEGFR2, as well as HIF1
and metabolic indicators of ischemia were similar in skeletal muscle of rabbit hind legs in the presence or absence of femoral artery ligation. Further analysis using hemodynamic methods demonstrated that the continuous infusion of VEGF did not improve collateral formation, yet the administration of monocyte chemotactic protein-1 (MCP1) significantly improved collateral conductance.10 Because mononuclear cells are well described as a source of the prototype members of the FGF gene family,11,12 it is reasonable to suggest that mononuclear cell infiltration of ischemic tissue may be an important contributor to arteriogenesis. The ability of FGF to be released into the extracellular compartment in response to cellular stress13 and tissue injury14 is consistent with this premise and, as a result, may provide the requisite mitogenic potential for arteriogenesis as a late response signal. Thus, we suggest that in response to tissue ischemia, VEGF gene expression may be responsible for mediating the immediate-early angiogenic response whereas MCP1 and/or other members of the CC and CXC chemokine families may facilitate the initiation of the mid-to-late response by the recruitment of mononuclear cells for the delivery of FGF as a mediator of the mid-to-late arteriogenic response.15,16 Because this hypothesis requires the presence of a signal that limits the angiogenic activity of VEGF, it is anticipated that a dominant-negative effector(s) of VEGF signaling may be present during the initiation of the mid-to-late MCP1 response. Although the nature of these dominant-negative effectors is not known, it is possible that this may include the expression of alternatively spliced forms of the VEGFR transcripts encoding the extracellular domains of these receptors that are known to function as dominant-negative effectors of VEGF-mediated signaling.17
The hydrolytic remodeling of the extracellular matrix, as well as the expression and function of cell fate determination genes, may be additional important components of the immediate-early angiogenic response and mid-to-late arteriogenic responses because these components may contain additional temporal and divergent features responsible for regulating the on-site activities of VEGFs, the CC and CXC chemokines, and FGFs, including the functions of the glycosylaminoglycans. For the successful development of any angiogenic or arteriogenic therapy, it is important to consider that the on-site delivery of these hormonal signals may be a key feature for their ability to integrate and cooperate with other on-site receptor-mediated signaling pathways. Indeed, the relatively short half-life that most polypeptide growth factors exhibit in the circulatory system after bolus intravascular administration18,19 should be a significant concern for design of any future therapeutic protocol because the inability to achieve sufficiently high levels of the polypeptide growth factor in the appropriate target tissue is unlikely. Whether the continuous local delivery of any polypeptide growth factor using an osmotic pump, a gene therapy strategy, or an alternative approach actually results in a net increase in the levels of the polypeptide growth factor within the target tissue should be clarified by preclinical studies. Indeed, the inability to achieve critical on-site levels of polypeptide growth factors in a target tissue after bolus intravenous injection may have been the major reason for the disappointing results of the clinical trials using VEGF and the major reason for the success of the FGF prototypes to augment human collateral blood vessel growth following the direct cardiac injection of the polypeptides.20,21
Although the results of Deindl et al10 argue that VEGF may not directly promote the growth of collateral arteries, it is likely that VEGF may still contribute to arteriogenesis since VEGF is indeed a potent stimulator of angiogenesis and an angiogenic response precedes arteriogenesis. One might anticipate that with the growth of new capillaries, the demand for blood flow may be expected to increase in the artery feeding the capillary bed. In order to maintain a constant level of shear stress, the artery should undergo positive remodeling, which requires arterial growth.22 Indeed, it is highly likely that in the absence of angiogenesis, there may be limited, if any, arteriogenesis. Because increases in arterial blood flow have been shown to induce remodeling in association with arterial growth in the absence of an ischemic situation, a known mediator of VEGF gene expression, it is also possible that the function of VEGF may be attenuated by receptor-dependant mechanisms including the expression of dominant-negative forms of VEGFR through combinatorial splicing or repression of specific VEGFR gene expression. In our own arteriogenic studies, we observed significant expression of the VEGFR1 transcript in migrating and proliferating ECs,23 yet we were unable to detect the presence of the VEGFR2 transcript, which has been shown to be important in mediating the mitogenic activity of VEGF. Although arterial EC were able to respond to infused VEGF with an increase in vascular permeability, we failed to observe an increase in either EC proliferation or endothelial outgrowth.23 Likewise, VEGFR1 is also expressed in neointimal SMCs, but these cells do not respond to VEGF as a mitogenic signal.24 In contrast, the infusion of FGF2 into these arteries resulted in significant increases in EC and SMC proliferation.25,26
Expression of MCP1 in the presence of adhering monocytes/macrophages has been observed in proliferating endothelium and smooth muscle,27,28 and the observation by Deindl et al10 that MCP1 was able to function as a mediator of arteriogenesis is quite interesting in that regard because it enables one to anticipate the function of other polypeptide cytokines that are known to be modifiers of EC and SMC migration, growth, and differentiation. Perhaps most notable are the members of the IL gene family and CXC chemokine family, which are known to function as EC cytokines.29,30 Indeed, it will be interesting to determine whether these proinflammatory EC cytokines can function to substitute for MCP1 and modify arteriogenesis or whether MCP1 is able to regulate the expression of either members of the IL gene family or other proinflammatory cytokine genes.
Acknowledgments
This work was supported by NIH Grants AG98503, HL35627, and HL32348 (to T.M.) and RR15555 (to V.L. and T.M.).
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
References
1.
Buschmann I, Schaper W. Arteriogenesis versus angiogenesis: two mechanisms of vessel growth. News Physiol Sci. 1999; 14: 121–125.
2. Carmeliet P. Mechanisms of angiogenesis and arteriogenesis. Nat Med. 2000; 6: 389–395.[Medline] [Order article via Infotrieve]
3. Buschmann I, Schaper W. The pathophysiology of the collateral circulation (arteriogenesis). J Pathol. 2000; 190: 338–342.[Medline] [Order article via Infotrieve]
4.
Hershey JC, Baskin EP, Glass JD, Hartman HA, Gilberto DB, Rogers IT, Cook JJ. Revascularization in the rabbit hindlimb: dissociation between capillary sprouting and arteriogenesis. Cardiovasc Res. 2001; 49: 618–625.
5. 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]
6.
Lazarous DF, Shou M, Stiber JA, Hodge E, Thirumurti V, Goncalves L, Unger EF. Adenoviral-mediated gene transfer induces sustained pericardial VEGF expression in dogs: effect on myocardial angiogenesis. Cardiovasc Res. 1999; 44: 294–302.
7. Takeshita S, Pu L-Q, Stein LA, Sniderman AD, Bunting S, Ferrara N, Isner JM, Symes JF. Intramuscular administration of vascular endothelial growth factor induces dose-dependent collateral artery augmentation in a rabbit model of chronic limb ischemia. Circulation. 1994; 90: 228–234.
8. 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.
9.
Schwarz ER, Speakman MT, Patterson M, Hale SS, Isner JM, Kedes LH, Kloner RA. 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. 2000; 35: 1323–1330.
10.
Deindl E, Buschmann I, Hoefer IE, Podzuweit T, Boengler K, Vogel S, van Royen N, Fernandez B, Schaper W. Role of ischemia and of hypoxia-inducible genes in arteriogenesis after femoral artery occlusion in the rabbit. Circ Res. 2001; 89: 779–786.
11.
Sano H, Forough R, Maier JA, Case JP, Jackson A, Engleka K, Maciag T, Wilder RL. Detection of high levels of heparin binding growth factor-1 (acidic fibroblast growth factor) in inflammatory arthritic joints. J Cell Biol. 1990; 110: 1417–1426.
12.
Blotnick S, Peoples GE, Freeman MR, Eberlein TJ, Klagsbrun M. T lymphocytes synthesize and export heparin-binding epidermal growth factor-like growth factor and basic fibroblast growth factor, mitogens for vascular cells and fibroblasts: differential production and release by CD4+ and CD8+ T cells. Proc Natl Acad Sci U S A. 1994; 91: 2890–2894.
13.
Tarantini F., Micucci I, Bellum S, Landriscina M, Garfinkel S, Prudovsky I, Maciag T. SThe precursor but not the mature form of IL1 blocks the release of FGF1 in response to heat shock. J Biol Chem. 2001; 276: 5147–5151.
14. Lindner V, Olson NE, Clowes AW, Reidy MA. Inhibition of smooth muscle cell proliferation in injured rat arteries: interaction of heparin with basic fibroblast growth factor. J Clin Invest. 1992; 90: 2044–2049.
15. Arras M, Ito WD, Scholz D, Winkler B, Schaper J, Schaper W. Monocyte activation in angiogenesis and collateral growth in the rabbit hindlimb. J Clin Invest. 1998: 101: 40–50.[Medline] [Order article via Infotrieve]
16.
Ito WD, Arras M, Winkler B, Scholz D, Schaper J, Schaper W. Monocyte chemotactic protein-1 increases collateral and peripheral conductance after femoral artery occlusion. Circ Res. 1997; 80: 829–837.
17.
Kendall RL Thomas KA. Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor. Proc Natl Acad Sci U S A. 1993; 90: 10705–10709.
18.
Rosengart TK, Kuperschmid JP, Maciag T, Clark RE. Pharmacokinetics and distribution of heparin-binding growth factor I (endothelial cell growth factor) in the rat. Circ Res. 1989; 64: 227–234.
19.
Lazarous DF, Shou M, Stiber JA, Dadhania DM, Thirumurti V, Hodge E, Unger EF. Pharmacodynamics of basic fibroblast growth factor: route of administration determines myocardial and systemic distribution. Cardiovasc Res. 1997; 36: 78–85.
20.
Schumacher B, Pecher P, von Specht BU, Stegmann T. Induction of neoangiogenesis in ischemic myocardium by human growth factors: first clinical results of a new treatment of coronary heart disease. Circulation. 1998; 97: 645–50.
21.
Pecher P, Schumacher BA. Angiogenesis in ischemic human myocardium: clinical results after 3 years. Ann Thorac Surg. 2000; 69: 1414–1419.
22.
Tuttle JL, Nachreiner RD, Bhuller AS, Condict KW, Connors BA, Herring BP, Dalsing MC, Unthank JL. Shear level influences resistance artery remodeling: wall dimensions, cell density, and eNOS expression. Am J Physiol Heart Circ Physiol. 2001; 281: H1380–H1389.
23.
Lindner V, Reidy MA. Expression of VEGF receptors in arteries after endothelial injury and lack of increased endothelial regrowth in response to VEGF. Arterioscler Thromb Vasc Biol. 1996; 16: 1399–1405.
24.
Couper LL, Bryant SR, Eldrup-Jorgensen J, Bredenberg CE, Lindner V. Vascular endothelial growth factor increases the mitogenic response to fibroblast growth factor-2 in vascular smooth muscle cells in vivo via expression of fms-like tyrosine kinase-1. Circ Res. 1997; 81: 932–939.
25. Lindner V, Majack RA, Reidy MA. Basic fibroblast growth factor stimulates endothelial regrowth and proliferation in denuded arteries. J Clin Invest. 1990; 85: 2004–2008.
26.
Lindner V, Lappi DA, Baird A, Majack RA, Reidy MA. Role of basic fibroblast growth factor in vascular lesion formation. Circ Res. 1991; 68: 106–113.
27.
Wempe F, Lindner V, Augustin HG. Basic fibroblast growth factor (bFGF) regulates the expression of the CC chemokine monocyte chemoattractant protein-1 (MCP1) in autocrine- activated endothelial cells. Arterioscler Thromb Vasc Biol. 1997; 17: 2471–2478.
28.
Landry DB, Couper LL, Bryant SR, Lindner V. Activation of the NF-
B and IB system in smooth muscle cells after rat arterial injury. Induction of vascular cell adhesion molecule-1 and monocyte chemoattractant protein-1. Am J Pathol. 1997; 151: 1085–1095.[Abstract]
29. Liekens S, De Clercq E, Neyts J. Angiogenesis: regulators and clinical applications. Biochem Pharmacol. 2001; 61: 253–270.[Medline] [Order article via Infotrieve]
30. Keane MP, Strieter RM. The role of CXC chemokines in the regulation of angiogenesis. Chem Immunol. 1999; 72: 86–101.[Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  T. Korff, J. Braun, D. Pfaff, H. G. Augustin, and M. Hecker Role of ephrinB2 expression in endothelial cells during arteriogenesis: impact on smooth muscle cell migration and monocyte recruitment Blood, July 1, 2008; 112(1): 73 - 81. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. van Weel, M. M.L. Deckers, J. M. Grimbergen, K. J.M. van Leuven, J. H.P. Lardenoye, R. O. Schlingemann, G. P. van Nieuw Amerongen, J. H. van Bockel, V. W.M. van Hinsbergh, and P. H.A. Quax Vascular Endothelial Growth Factor Overexpression in Ischemic Skeletal Muscle Enhances Myoglobin Expression In Vivo Circ. Res., July 9, 2004; 95(1): 58 - 66. [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]
|
|
|
|
 |
|
 N. V. Soucy, M. A. Ihnat, C. D. Kamat, L. Hess, M. J. Post, L. R. Klei, C. Clark, and A. Barchowsky Arsenic Stimulates Angiogenesis and Tumorigenesis In Vivo Toxicol. Sci., December 1, 2003; 76(2): 271 - 279. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. H. Laughlin, J. R. Turk, W. G. Schrage, C. R. Woodman, and E. M. Price Influence of coronary artery diameter on eNOS protein content Am J Physiol Heart Circ Physiol, April 1, 2003; 284(4): H1307 - H1312. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. A.U. Heilmann, T. Attmann, P. von Samson, H. Gobel, D. Marme, F. Beyersdorf, and G. Lutter Transmyocardial laser revascularization combined with vascular endothelial growth factor121 (VEGF121) gene therapy for chronic myocardial ischemia - do the effects really add up? Eur. J. Cardiothorac. Surg., January 1, 2003; 23(1): 74 - 80. [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]
|
|
|
|
|
|
S. Herzog, H. Sager, E. Khmelevski, A. Deylig, and W. D. Ito Collateral arteries grow from preexisting anastomoses in the rat hindlimb Am J Physiol Heart Circ Physiol, November 1, 2002; 283(5): H2012 - H2020. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.-J. Park, D. Kong, L. Iruela-Arispe, U. Begley, D. Tang, and J. B. Galper 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors Interfere With Angiogenesis by Inhibiting the Geranylgeranylation of RhoA Circ. Res., July 26, 2002; 91(2): 143 - 150. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||