Vascular Endothelial Growth Factor (VEGF) Receptor-2 Tyrosine 1175 Signaling Controls VEGF-induced von Willebrand Factor Release from Endothelial Cells via Phospholipase C-γ1- and Protein Kinase A-dependent Pathways

• Published in: The Journal of biological chemistry 2009-08, Vol.284 (35), p.23217
• Main Authors: Yan Xiong, Yingqing Huo, Chao Chen, Huiyan Zeng, Xiaofan Lu, Chaoliang Wei, Changgeng Ruan, Xiaoyu Zhang, Zhenqian Hu, Masabumi Shibuya, Jincai Luo
• Format: Article
• Language: English
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M109.019679

There is increasing evidence that vascular endothelial growth factor (VEGF) contributes to inflammation independent of its angiogenic functions. Targeting some of the components in endothelial Weibel-Palade bodies (WPBs) effectively inhibits VEGF-induced inflammation, but little is known about how VEGF regulates WPB exocytosis. In this study, we showed that VEGF receptor-2 (VEGFR2), but not VEGFR1, is responsible for VEGF-induced release of von Willebrand factor (vWF), a major marker of WPBs. This is in good contrast to VEGF-stimulated interleukin-6 release from endothelium, which is selectively mediated through VEGFR1. We further demonstrated that VEGFR2-initiated phospholipase C-γ1 (PLCγ1)/calcium signaling is important but insufficient for full vWF release, suggesting the possible participation of another effector pathway. We found that cAMP/protein kinase A (PKA) signaling is required for full vWF release. Importantly, a single mutation of Tyr 1175 in the C terminus of VEGFR2, a tyrosine residue crucial for embryonic vasculogenesis, abolished vWF release, concomitant with defective activations of both PLCγ1 and PKA. These data suggest that Tyr 1175 mediates both PLCγ1-dependent and PKA-dependent signaling pathways. Taken together, our results not only reveal a novel Tyr 1175 -mediated signaling pathway but also highlight a potentially new therapeutic target for the management of vascular inflammation.