The Role of VEGFR-1 During Murine Postnatal Angiogenesis

Date of Completion

January 2011


Biology, Cell|Health Sciences, Human Development




Angiogenesis is the process by which new blood vessels emerge from existing vessels. Failure to mimic the complex angiogenic process and produce natural blood vessels is one of the main obstacles preventing advancements in the fields of pro-angiogenic therapies and tissue engineering. The vascular endothelial growth factor (VEGF) family of molecules defines some of the main regulators involved in orchestrating both normal developmental angiogenesis as well as pathological angiogenesis under disease conditions. The control and understanding of their individual roles is paramount to making progress in vascular disease treatments. ^ VEGF is a potent angiogenic cytokine that interacts with many molecules including VEGF Receptor-1 (Flt-1/VEGFR-1) and VEGF Receptor-2 (KDR/Flk-1/VEGFR-2). During embryonic development, VEGFR-1 and VEGFR-2 have been characterized as negative and positive regulators of angiogenic functions, respectively. Despite distinct embryonic contributions, the role of VEGFR-1 in neonatal and postnatal development remains ambiguous, and its function during pathological angiogenesis ischemia is even more obscure. To aid in investigations into the role of VEGFR-1 during later stages of development and under pathophysiological environments, a Vegfr-1 conditional knockout mouse line was generated using BAC recombineering techniques. ^ VEGFR-1 deficiency led to increased angiogenesis in postnatal and adult mice. Surprisingly, the vessels were functional and mature, despite upregulation of endothelial cell proliferation, tip cell formation, and branching morphogenesis. When challenged with experimentally induced cardiac ischemia and oxygen induced retinopathy, VEGFR-1 deficiency promoted angiogenesis in the cardiomyopathy model and increased the neovascular response in ischemic retinas. ^ Treatment with a VEGFR-2 specific inhibitor or introduction of heterozygous loss of VEGFR-2 was able to moderate the increased angiogenesis in VEGFR-1 deficient mice. Molecularly, these responses are most likely due to increased abundance of VEGFR-2 and phosphorylation of Akt, a downstream signaling molecule. ^ Overall, systemic loss of VEGFR-1 does not severely affect health in mice nor does it result in aberrant blood vessels. Mechanistically, this study demonstrates that an important role of VEGFR-1 in postnatal tissues is to modulate VEGFR-2 concentrations and signaling. These results shed light on the mechanism of VEGFR-1-regulated postnatal angiogenesis and contribute to the development of VEGFR-1 as a potential pharmacological target for angiogenic therapies. ^