Role of vascular endothelial growth factor-A in collateral growth and development Public Deposited

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  • March 21, 2019
  • Clayton, Jason Allen
    • Affiliation: School of Medicine, Department of Cell Biology and Physiology
  • Ischemic vascular disease is the leading cause of morbidity and mortality in the United States. Current therapies rely on invasive surgical procedures. Arteriogenesis, or collateral artery growth, has the potential to greatly improve the outcome of patients with ischemic vascular disease by providing an endogenous bypass circulation. However, the underlying biology of arteriogenesis remains poorly understood. There are conflicting animal and clinical reports of VEGF administration improving outcomes or increasing adverse effects. Because of systemic VEGF's pleiotropic functions, we hypothesized that local endogenous VEGF directly promotes the growth of collaterals. In addition, because of its role in vascular branching morphogenesis we hypothesized that VEGF may also play a role in the embryonic development of collaterals. To test these hypotheses, we used mouse models genetically targeting the VEGF pathway (VEGFhi/+, VEGFlo/+, VEGFR-1+/-, and VEGFR-2+/-) and local inhibitory approaches combining plasmid electroporation of Cre recombinase in VEGFloxP/loxP mice and FltIgG (VEGF-trap) in wild-type mice. We have found that VEGFR-1 is the principle VEGF receptor responsible for mediating arteriogenesis through recruitment of circulating monocytes. We also found impaired arteriogenesis in mice genetically expressing low levels of VEGF (VEGFlo/+). In addition, Cre-mediated deletion of VEGF in the adductor led to impaired plantar perfusion recovery, increased ischemic appearance, and impaired limb use. Expression of FltIgG in the adductor also increased ischemic appearance and impaired limb use. There was also evidence of impaired collateral perfusion despite normal plantar perfusion. We found a VEGF genotype - collateral density relationship, such that VEGFhi/+ mice had greater collaterals while VEGFlo/+ mice had fewer. Developmentally, we found that VEGFhi/+ and wild-type mice were born with more collaterals than VEGFlo/+. Interestingly in wild-type and VEGFlo/+ mice collateral density declined over the first 3 weeks of life at which time the adult density was attained, while VEGFhi/+ mice retained their collaterals from birth. These data suggest that VEGF levels must be maintained high enough to establish optimal collateral density and to ensure maturation of nascent collaterals during development. We identified a key role for VEGFR-1 in mediating collateral enlargement in ischemia. In addition, we have identified the first molecule, VEGF, responsible for the formation of native collaterals in healthy tissue.
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  • Faber, James
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