doi: 10.1161/01.RES.0000338258.90706.2c
© 2008 American Heart Association, Inc.
Editorials |
Vascular Endothelial Growth Factor and the Collateral Circulation
The Story Continues
From the Department of Integrative Medical Sciences, Northeastern Ohio Universities College of Medicine, Rootstown.
Correspondence to William M. Chilian, PhD, Department of Integrative Medical Sciences, Northeastern Ohio Universities College of Medicine, 4209 State Rd 44, Rootstown, Ohio 44272. E-mail wchilian{at}neoucom.edu
See related article, pages 1027–1036
Key Words: collateral circulation • growth factors
The Greek philosopher Socrates once mused that the more one knows, the more one does not know. An extension of this philosophy could be applied to our knowledge of the myriad actions and effects of vascular endothelial growth factor (VEGF). It seems that the more we understand about VEGF, the less we really comprehend about this complicated many-faceted, growth factor/cytokine/morphogen/survival factor/permeability factor, protein!
Originally VEGF was described as vascular permeability factor, a glycoprotein with a mass of 40 kDa, which induced macromolecular leakage in the circulation.1–4 At approximately the same time as the permeability effects were elucidated, the potent angiogenic activities of VEGF were also uncovered, leading to the suggestion that we name it vasculotropin.5–8 Since these reports in the late 1980s and early 1990s, publications related to the actions, signaling, and regulation of VEGF, have proliferated to now exceed 24 000. Although the initial isoforms described were of the VEGF-A family, the VEGF clan has since grown to 5 (VEGF-A, VEGF-B, VEGF-C, VEGF-D, and PLGF),9 and new "offspring" continue to appear at the doorstep.10,11 The remaining discussion here focuses on VEGF-A family members, often referred to collectively as simply VEGF.
The majority of publications have reported that the actions of VEGF are confined largely to endothelial cells, where it is critical for angiogenesis and embryonic vasculogenesis.12,13 However, as studies uncovered the myriad additional actions of VEGF an enigma surfaced, vis-à-vis, VEGF was found to also play a role in arterial (ie, smooth muscle cell) growth, both in the embryo and in the adult.14–21 The puzzling aspect of this observation stems from the fact that most investigations have found that vascular smooth muscle does not express VEGF receptors,22 although 1 report suggested that VEGFR1 and VEGFR2 are expressed in vascular smooth muscle.23 The consensus that VEGF receptors are not expressed by these cells, but that VEGF contributes to the assembly and growth of the arterial wall in the embryo and maturation of collateral vessels in the adult, in a sense, remains as much an enigma today as it did a decade ago. Therefore, indeed, we have learned more about VEGF, but along the way we have also raised more questions.
In this issue of Circulation Research, Clayton et al have advanced our understanding about the role of VEGF in formation of the native collateral network and in the abluminal expansion of collaterals in response to ischemia (arteriogenesis).24 The investigators studied various targeted murine mutants: mice heterozygous for VEGF receptor-1 (VEGFR-1+/–), VEGF receptor-2 (VEGFR-2+/–), and overexpressing (VEGFhi/+) and underexpressing VEGF-A (VEGFlo/+). Animals were subjected to hindlimb ischemia by femoral artery ligation. Interestingly, various indices of hindlimb collateralization and angiogenesis (ischemic scores, recovery of hindlimb perfusion, pericollateral leukocyte accumulation, collateral enlargement, and angiogenesis) were not different between wild-type and VEGFR-2+/– mice, perhaps because of receptor reserve. In contrast, mice heterozygous for VEGFR-1 showed impaired perfusion recovery, pericollateral leukocyte accumulation, and collateral enlargement, and worse ischemic scores but comparable angiogenesis. These results provide a compelling argument for the involvement of VEGFR1 (flt-1) in collateral vessel expansion in ischemia.
Perhaps even more fascinating, mice underexpressing VEGF (VEGFlo/+) had 2-fold lower perfusion immediately after ligation and a fewer number of collaterals visible by angiography. This finding supports a new, exciting concept that VEGF is regulating the formation of the native collateral circulation. This concept was also supported by the observation that VEGFlo/+ mice had poorer subsequent growth of the collateral circulation (compared to wild type) after ligation. Also supporting the role of VEGF in native collateral formation was the observation that mice overexpressing VEGF (VEGFhi/+) had substantially higher greater perfusion immediately after ligation, more angiographically visible collaterals, and improved recovery of perfusion over time. Similar observations were made in the cerebral circulation, ie, VEGFlo/+ mice were born with fewer collaterals, many of which evidenced regression during the perinatal period, leading to fewer collaterals in the adult and 2-fold larger infarctions after middle cerebral artery ligation compared to the VEGFhi/+ mice. These observations convincingly demonstrate that VEGF-A determines formation of native collaterals in healthy tissues. The potential significance of these observations relates to observation that the magnitude of enlargement of individual collaterals in ischemic disease is influenced by the extent of the initial collateral network. Although this observation was anecdotally accepted for years (refer to Figure 2 in the article by Toyota et al19), a recent study unequivocally established this relationship.25 The implication of these observations is that if the native collateral number or conductance is low, growth of the collateral circulation in disease is poor, and the converse also holds when the native conductance is high. Perhaps the findings of Clayton et al24 provide the basis for a screen predicting that patients may be at more risk for stroke, myocardial infarction, and/or peripheral vascular disease in the context of inherent genetic differences in VEGF-A expression. It would follow that reduced expression of VEGF-A or altered isoform expression pattern, eg, from a polymorphism in its promoter or splicing machinery, may impair native collateral formation, thus creating a higher risk for a catastrophic event in the event of occlusive disease or a thrombus. Thus, the study of Clayton et al has certainly advanced our understanding of the role of VEGF in the collateral circulation, but, at the same time, it has given all of us much more to consider when evaluating or predicting arteriogenic responses.
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Acknowledgments |
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Sources of Funding
Supported by the NIH grants HL32788 and HL43617.
Disclosures
None.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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Related Article:
Circ. Res. 2008 103: 1027-1036.
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