BACKGROUND: Vascular endothelial growth factor (VEGF) plays a key role in regulating angiogenesis, and this process is largely dependent on the newly formed extracellular matrix (ECM). The levels of vitronectin (VN) are increased in patients with various cardiovascular diseases. A role for VN in regulating VEGF-induced angiogenesis has not been previously reported. We tested the hypothesis that VN regulates VEGFR-2 activation via effects on αvβ3, thus contributing to angiogenesis. METHODS: We used a 3-dimensional angiogenesis assay, and examined the effects of VN on VEGF-mediated angiogenesis in aortic endothelial cells (ECs) isolated from wild-type and VN-deficient mice. RESULTS: The addition of multimeric VN significantly enhanced VEGF-induced increases in EC migration and capillary formation. In vitro, Vn(-/-) ECs migrated significantly slower than wild-type ECs. The addition of VN to Vn(-/-) ECs increased EC migration and augmented the promigratory effect of VEGF in a manner that involved VEGFR-2 and Src signaling. Analysis of the mechanisms involved revealed that multimeric VN, but not monomeric VN, binds VEGF and enhances VEGF-induced VEGFR-2/Src activation in ECs. CONCLUSION: These results underscore the importance of VN in the regulation of angiogenesis induced by VEGF.
BACKGROUND:Vascular endothelial growth factor (VEGF) plays a key role in regulating angiogenesis, and this process is largely dependent on the newly formed extracellular matrix (ECM). The levels of vitronectin (VN) are increased in patients with various cardiovascular diseases. A role for VN in regulating VEGF-induced angiogenesis has not been previously reported. We tested the hypothesis that VN regulates VEGFR-2 activation via effects on αvβ3, thus contributing to angiogenesis. METHODS: We used a 3-dimensional angiogenesis assay, and examined the effects of VN on VEGF-mediated angiogenesis in aortic endothelial cells (ECs) isolated from wild-type and VN-deficientmice. RESULTS: The addition of multimeric VN significantly enhanced VEGF-induced increases in EC migration and capillary formation. In vitro, Vn(-/-) ECs migrated significantly slower than wild-type ECs. The addition of VN to Vn(-/-) ECs increased EC migration and augmented the promigratory effect of VEGF in a manner that involved VEGFR-2 and Src signaling. Analysis of the mechanisms involved revealed that multimeric VN, but not monomeric VN, binds VEGF and enhances VEGF-induced VEGFR-2/Src activation in ECs. CONCLUSION: These results underscore the importance of VN in the regulation of angiogenesis induced by VEGF.
Authors: Debanjan Mukherjee; Ganesh Wagh; Mayssa H Mokalled; Zacharias Kontarakis; Amy L Dickson; Amey Rayrikar; Stefan Günther; Kenneth D Poss; Didier Y R Stainier; Chinmoy Patra Journal: Development Date: 2021-01-18 Impact factor: 6.862