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Circulation Research. 2001;88:1099-1101
doi: 10.1161/hh1101.092472
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(Circulation Research. 2001;88:1099.)
© 2001 American Heart Association, Inc.

Editorial

Harmonic Interplay of Angiogenic Growth Factors in the Development of Coronary Blood Vessels

Mitsuhiro Yokoyama, Tetsuaki Hirase

From the Division of Cardiovascular and Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.

Correspondence to Mitsuhiro Yokoyama, MD, PhD, Professor, Division of Cardiovascular and Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. E-mail yokoyama{at}med.kobe-u.ac.jp


Key Words: vascular endothelial growth factor • basic fibroblast growth factor • angiogenesis • antiangiogenesis

Organized blood vessel formation is essential for development and physiological function of organs. Blood vessel formation is composed of complicated and sequential processes initiated by vasculogenesis in which endothelial progenitor cells differentiate, proliferate, and subsequently assemble into primitive tubular networks.1 2 3 Vasculogenesis is followed by angiogenesis, wherein vascular networks remodel into more complex networks through dilatation, sprouting, and bridging.1 2 3 Another form of blood vessel growth after birth is arteriogenesis. Arteriogenesis is defined as structural enlargement and remodeling by growth of preexisting arteriolar connections.2 3 4 During arteriogenesis, smooth muscle cells migrate and assemble along the preexisting tubes to form mature, stabilized vessels with vasomotor functions.2 3 4 Although vasculogenesis has been observed solely in the embryonic stage, the identification of circulating endothelial precursor cells indicates the contribution of vasculogenesis in blood vessel formation in adult tissue.5

Coronary blood vessels originate from endothelial precursor cells migrating to the epicardium in the embryonic stage, during which coronary vasculogenesis takes place.6 7 The vascular tubes formed by vasculogenesis grow by angiogenic sprouting and mature in the interaction with pericytes. The result is coronary capillary formation. After capillary formation, vascular plexuses, which appear in the outflow tract region, generate continuous tubes and penetrate into the aorta. Along these preexisting vessels, recruited smooth muscle cells migrate and cover the tubes from epicardial to endocardial direction. Then vessels form coronary veins and arteries.6 7 During the early postnatal period, marked capillary growth proceeds in myocardium, and maturation of arteries occurs mostly after birth.6 7

Because most of the works in this field have focused on polypeptide angiogenic factors until recently, angiogenic growth factors, such as vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF), have been highlighted as key regulators of blood vessel formation and maintenance in development and physiology.8 9 Novel genetic approaches using gene ablation and transgene expression have made enormous contributions in understanding that VEGF is an indispensable requirement for both vasculogenesis and angiogenesis.10 11 12 13 14 FGF also promotes angiogenesis, as revealed in various types of angiogenesis assays both in vitro and in vivo, whereas the ablation of FGF did not cause severe vascular defects.15 16 17 18 19 Angiopoietins also work as an angiogenic factor in maturing and stabilizing vessels at later stages of vascular development.8 9 On the other hand, recent advances have identified angiostatin, an internal fragment of plasminogen,20 and endostatin, a proteolytic fragment of collagen XVIII,21 as angiogenesis inhibitors. Both angiostatin and endostatin have been shown to possess multiple antiangiogenic effects in vitro and in vivo, including an induction of tumor regression in vivo.20 21 Additionally, multiple factors, such as extracellular matrix and mechanical factors like shear stress, are considered to modulate vessel formation. Hypoxia is also a strong inducer of angiogenesis, mostly through hypoxia-inducible factor-dependent expression of VEGF, its receptors, and other angiogenic factors.2 3

In this issue of Circulation Research, Tomanek et al22 demonstrate in vivo interplay of VEGF and basic FGF (bFGF) in coronary vessel development through a unique approach. Tomanek et al22 tried to partially block the actions of VEGF and bFGF in rat myocardium by neutralizing antibodies against VEGF and bFGF during the early stage of the postnatal period, when angiogenic sprouting leading to capillary growth actively progresses. Although the antibodies were administered through intraperitoneal injection, the delivery of the antibodies to the myocardium was verified. The ventricular weights and histology of the hearts, including cardiomyocytes, vascular cells, and extracellular matrix, in the treated rats were unaffected by the neutralizing anti-VEGF and anti-bFGF antibodies and the combination of both antibodies. Tomanek et al22 could then observe a physiological remodeling of coronary vessels attributable to modified actions of the growth factors. However, a pathological remodeling secondary to changed myocardial oxygen demand could not be observed. In this model, it was shown that both VEGF and bFGF are essential for capillary growth. The careful analysis on the morphometry of coronary vessels revealed the decrease of capillary growth to {approx}80% of control by the treatment with anti-VEGF, anti-FGF, or a combination of both. The complete loss of VEGF signaling by the ablation of VEGF or its functional receptor VEGFR-2 failed to form a vasculature and had fewer endothelial cells.11 12 13 Inducible Cre-loxP–mediated VEGF gene targeting in newborn mice resulted in impaired organ development.14 Therefore, the inhibition of VEGF and bFGF by the neutralizing antibodies must be partial, and the partial reduction of VEGF during the early postnatal stage, when angiogenesis is active, can be expected to form decreased capillaries in which endothelial cells are a major component. Accumulating evidence of the angiogenic property of bFGF supports this observation.15 16 17 18 19 The interplay of VEGF and bFGF in the promotion of angiogenesis has been characterized, and angiogenic actions of bFGF are shown to depend partially on VEGF.23 In the study by Tomanek et al,22 the effects of anti-VEGF and anti-bFGF antibodies are not additive on the reduced capillary growth. This may be because the actual neutralization in vivo of each growth factor is not equivalent.

As shown by Tomanek et al,22 bFGF inhibition, but not VEGF inhibition, significantly decreased arteriolar growth. This observation is not surprising, because bFGF plays important roles to promote the differentiation and recruitment of smooth muscle cells,2 15 which are essential for arteriolar growth. Again, because it is impossible for us to evaluate to what extent and how long VEGF and bFGF actions were neutralized in vivo by the antibodies, there is a possibility that we underestimate the involvement of VEGF in arteriole formation. The dual inhibition of both VEGF and bFGF caused a shift in dimension of arterioles from smaller to larger but not a decrease in arteriolar growth. Therefore, controlled actions of both VEGF and bFGF seem to regulate arteriolar diameter. According to the dual growth factor inhibition, both arteriolar growth and the vascular morphology—including wall thickness, which indicates relevance to the recruitment of smooth muscle cells—were unaffected. The shift in diameter of arterioles might be attributable to an adaptation of vessels to maintain coronary circulation, whereas additional studies are required to clarify the determinants of vascular dimension and the involvement of growth factors.

In the study by Tomanek et al,22 several questions remain to be answered. Is harmonic interplay of VEGF and bFGF necessary and sufficient for the maturation and maintenance of coronary vessels in adult rats after the early postnatal stage? Once coronary vessels undergo physiological remodeling in the postnatal stage, are the maturation and the maintenance of coronary vessels perturbed in the later adult stage? To address these issues, longer observations of coronary vascular trees in treated rats are necessary. The VEGF or bFGF inhibition for a longer duration or during the later postnatal stage is required. In addition, the involvement of other angiogenic factors as well as angiogenesis inhibitors should be investigated. The answers to the aforementioned questions are crucial elements in the ability to predict the outcome of long-term growth factor inhibition in blood vessel development.

Recently, the results of early clinical trials in therapeutic angiogenesis for peripheral vascular disease and coronary artery disease have been reported,24 and limited but promising results have had a tremendous impact on additional investigations. On the other hand, the results deserve more intensive research on potential risks involved. There is the possibility for improvement by modifying doses, routes, and duration of administration. The choice of angiogenic agents, genes, or proteins, whether single or multiple, is also essential. We should note that therapeutic angiogenesis has been focused mainly on the induction of capillary formation. To construct and maintain physiological blood circulation, capillaries as well as arterioles with vasomotor functions must be properly formed.4 However, newly formed capillaries are prone to be destroyed because of the lack of surrounding smooth muscle cells. Therefore, arteriogenesis should coincide with angiogenesis. Strategies to trigger not only angiogenesis but also arteriogenesis could be more beneficial to therapeutic angiogenesis. Combined and sequential administration of multiple factors would be ideal. Along this line, the study by Asahara et al25 provides evidence that angiopoietins enhance the angiogenic actions of VEGF in vivo. Multiple angiogenic/antiangiogenic factors, including unknown factors, are biologically potent and constitute a complex orchestration for physiology of the vascular network.8 Timing, duration, and controlled targeting to the organs of angiogenic actions are key factors for optimal outcomes and prevention of deleterious effects. One such example reported that unregulated, continuous delivery of VEGF to the myocardium caused the formation of hemangioma and death in mice.26 Growth factor antagonism is a novel therapeutic strategy for cardiovascular diseases, such as atherogenesis and restenosis.27 28 29 30 Certainly profound insights are required into therapeutic angiogenesis/antiangiogenesis by modulating actions of angiogenic/antiangiogenic factors to obtain favorable and more physiological results. The present study by Tomanek et al22 leads us to appreciate the conclusion that actions of angiogenic growth factors must be strictly regulated and harmonized for development during the early postnatal period of functional coronary vessels possessing normal structures.

Footnotes

The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

References

  1. Risau W. Mechanisms of angiogenesis. Nature. 1997;386:671–674.[Medline] [Order article via Infotrieve]
  2. Conway EM, Collen D, Carmeliet P. Molecular mechanisms of blood vessel growth. Cardiovasc Res. 2001;49:507–521.[Free Full Text]
  3. Carmeliet P. Mechanisms of angiogenesis and arteriogenesis. Nat Med. 2000;6:389–395.[Medline] [Order article via Infotrieve]
  4. van Royen N, Piek JJ, Buschmann I, Hoefer I, Voskuil M, Schaper W. Stimulation of arteriogenesis: a new concept for the treatment of arterial occlusive disease. Cardiovasc Res. 2001;49:543–553.[Abstract/Free Full Text]
  5. Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, Witzenbichler B, Schatteman G, Isner JM. Isolation of putative progenitor endothelial cells for angiogenesis. Science. 1997;275:964–967.[Abstract/Free Full Text]
  6. Tomanek RJ. Formation of the coronary vasculature: a brief review. Cardiovasc Res. 1996;31:E46–E51.
  7. Olivetti G, Anversa P, Loud AV. Morphometric study of early postnatal development in the left and right ventricular myocardium of the rat, II: tissue composition, capillary growth, and sarcoplasmic alterations. Circ Res. 1980;46:503–512.[Free Full Text]
  8. Gale NW, Yancopoulos GD. Growth factors acting via endothelial cell-specific receptor tyrosine kinases: VEGFs, angiopoietins, and ephrins in vascular development. Genes Dev. 1999;13:1055–1066.[Free Full Text]
  9. Yancopoulos GD, Davis S, Gale NW, Rudge JS, Wiegand SJ, Holash J. Vascular-specific growth factors and blood vessel formation. Nature. 2000;407:242–248.[Medline] [Order article via Infotrieve]
  10. Carmeliet P, Collen D. Transgenic mouse models in angiogenesis and cardiovascular disease. J Pathol. 2000;190:387–405.[Medline] [Order article via Infotrieve]
  11. Carmeliet P, Ferreira V, Breier G, Pollefeyt S, Kieckens L, Gertsenstein M, Fahrig M, Vandenhoeck A, Harpal K, Eberhardt C, Declercq C, Pawling J, Moons L, Collen D, Risau W, Nagy A. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature. 1996;380:435–439.[Medline] [Order article via Infotrieve]
  12. Ferrara N, Carver-Moore K, Chen H, Dowd M, Lu L, O’Shea KS, Powell-Braxton L, Hillan KJ, Moore MW. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature. 1996;380:439–442.[Medline] [Order article via Infotrieve]
  13. Shalaby F, Rossant J, Yamaguchi TP, Gertsenstein M, Wu XF, Breitman ML, Schuh AC. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature. 1995;376:62–66.[Medline] [Order article via Infotrieve]
  14. Gerber HP, Hillan KJ, Ryan AM, Kowalski J, Keller GA, Rangell L, Wright BD, Radtke F, Aguet M, Ferrara N. VEGF is required for growth and survival in neonatal mice. Development. 1999;126:1149–1159.[Abstract]
  15. Bikfalvi A, Klein S, Pintucci G, Rifkin DB. Biological roles of fibroblast growth factor-2. Endocr Rev. 1997;18:26–45.[Abstract/Free Full Text]
  16. 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.
  17. Fernandez B, Buehler A, Wolfram S, Kostin S, Espanion G, Franz WM, Niemann H, Doevendans PA, Schaper W, Zimmermann R. Transgenic myocardial overexpression of fibroblast growth factor-1 increases coronary artery density and branching. Circ Res. 2000;87:207–213.[Abstract/Free Full Text]
  18. Carmeliet P. Fibroblast growth factor-1 stimulates branching and survival of myocardial arteries: a goal for therapeutic angiogenesis? Circ Res. 2000;87:176–178.[Free Full Text]
  19. Miller DL, Ortega S, Bashayan O, Basch R, Basilico C. Compensation by fibroblast growth factor 1 (FGF1) does not account for the mild phenotypic defects observed in FGF2 null mice. Mol Cell Biol. 2000;20:2260–2268.[Abstract/Free Full Text]
  20. O’Reilly MS, Holmgren L, Shing Y, Chen C, Rosenthal RA, Moses M, Lane WS, Cao Y, Sage EH, Folkman J. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell. 1994;79:315–328.[Medline] [Order article via Infotrieve]
  21. O’Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, Flynn E, Birkhead JR, Olsen BR, Folkman J. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell. 1997;88:277–285.[Medline] [Order article via Infotrieve]
  22. Tomanek RJ, Sandra A, Zheng W, Brock T, Bjercke RJ, Holifield JS. Vascular endothelial growth factor and basic fibroblast growth differentially modulate early postnatal coronary angiogenesis. Circ Res. 2001;88:1135–1141.[Abstract/Free Full Text]
  23. Seghezzi G, Patel S, Ren CJ, Gualandris A, Pintucci G, Robbins ES, Shapiro RL, Galloway AC, Rifkin DB, Mignatti P. Fibroblast growth factor-2 (FGF-2) induces vascular endothelial growth factor (VEGF) expression in the endothelial cells of forming capillaries: an autocrine mechanism contributing to angiogenesis. J Cell Biol. 1998;141:1659–1673.[Abstract/Free Full Text]
  24. Epstein SE, Fuchs S, Zhou YF, Baffour R, Kornowski R. Therapeutic interventions for enhancing collateral development by administration of growth factors: basic principles, early results and potential hazards. Cardiovasc Res. 2001;49:532–542.[Abstract/Free Full Text]
  25. Asahara T, Chen D, Takahashi T, Fujikawa K, Kearney M, Magner M, Yancopoulos GD, Isner JM. Tie2 receptor ligands, angiopoietin-1 and angiopoietin-2, modulate VEGF-induced postnatal neovascularization. Circ Res. 1998;83:233–240.[Abstract/Free Full Text]
  26. Lee RJ, Springer ML, Blanco-Bose WE, Shaw R, Ursell PC, Blau HM. VEGF gene delivery to myocardium: deleterious effects of unregulated expression. Circulation. 2000;102:898–901.[Abstract/Free Full Text]
  27. Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med. 1995;1:27–31.[Medline] [Order article via Infotrieve]
  28. Waltenberger J. Modulation of growth factor action: implications for the treatment of cardiovascular diseases. Circulation. 1997;96:4083–4094.[Abstract/Free Full Text]
  29. Ferrara N, Alitalo K. Clinical applications of angiogenic growth factors and their inhibitors. Nat Med. 1999;5:1359–1364.[Medline] [Order article via Infotrieve]
  30. Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature. 2000;407:249–257.[Medline] [Order article via Infotrieve]



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