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Dynamic regulation of VEGF‐A signaling by co‐receptors and the extracellular matrix

Angiogenesis is a highly regulated process orchestrated by the complex vascular endothelial growth factor (VEGF) system, which is comprised of multiple isoforms and cell surface receptors. In addition, heparin/heparan sulfate (HS) proteoglycans and neuropilins (NRP) have been described as co‐receptors. In the present study we have characterized molecular interactions between the two most commonly expressed VEGF isoforms and their receptors and co‐receptors, using surface plasmon resonance (SPR). Our data suggest that heparin/HS plays different roles in the regulation of VEGF‐VEGFR complex formation depending on the receptor type. VEGFR2 is able to interact with VEGF165 bound by heparin, but interacts very weakly with heparin. VEGFR1 and NRP1 on the contrary, bind heparin independently of VEGF165. It appears heparin/HS play selective roles within each complex and could be key players in determining VEGF cellular response. NRP1 on the other hand, can interact directly with VEGFR1 and 2, alone or as a complex with VEGF165. Our results are also correlated to MAPK pathway activation in response to VEGF in endothelial cells. We propose that HS/heparin and NRP1 dictate the specific receptor type activated by VEGF and ultimately determine the biological response of the VEGF system. Supported by HL088572 and AHAF M2012014.