Effect Of VEGF-A On The Expressions Of Arterial And Venous Markers In Adult Endothelial Cells

Introduction:During vein graft adaptation to the arterial circulation, vascular endothelial growth factor (VEGF)-A expression transiently increases before becoming down-regulated; however the role of VEGF-A in venous remodeling is not clear. In addition, although VEGF-A stimulates angiogenesis and determines arterial identity in nascent arterial endothelial cells (EC), the role of VEGF-A in regulating identity in adult venous EC is also not clear. Therefore we examined the effects of VEGF-A on regulation of identity in adult venous EC.Methods and Results:VEGF-A (100ng/ml) inhibited expression of EphB4and stimulated expression of dll4but did not stimulate either notch or EphrinB2expression in adult venous EC. Pretreatment with VEGFR2neutralizing antibody abolished VEGF-stimulated down-regulation of EphB4but not the up-regulation of D114. Pretreatment with PD98059or wortmannin showed that VEGF-A down-regulation of EphB4and up-regulation of D114are MEK-ERK-dependent but PI3k-Akt-independent. Compared to VEGF-induced EphB4down-regulation and D114up-regulation in control EC, reduced EphB4signaling in heterozygous knockout (EphB4+/-) EC showed even further down-regulation of EphB4and up-regulation of D114.Discussion:Despite the genetic programming of arterial and venous endothelial cell fate, VEGF-A can repress venous identity in adult venous EC without induction of arterial identity. These changes in adult EC in vitro recapitulate the changes in identity described during vein graft adaptation to the arterial environment in vivo. Vein graft adaptation may depend on the plasticity of adult EC and their ability to integrate VEGF signaling pathways to properly alter vessel identity. EphB4may not be a passive marker of venous identity but may actively promote retention of venous identity by suppressing VEGF-A signaling in adult venous EC.