Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
Azienda Socio-sanitaria Territoriale Spedali Civili di Brescia, Brescia, Italy.
Angiogenesis. 2019 Nov;22(4):521-533. doi: 10.1007/s10456-019-09676-y. Epub 2019 Jul 30.
The Bone Morphogenetic Protein 4 (BMP4) regulates multiple biological processes, including vascular development and angiogenesis. Here, we investigated the role of Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) in mediating the angiogenic activity of BMP4. BMP4 induces a rapid relocation and phosphorylation of VEGFR2 on the endothelial cell membrane. These effects occur in the absence of a direct interaction of BMP4 and/or BMP receptors with VEGFR2. At variance, BMP4, by interacting with the BMPRI-II hetero-complex, induces c-Src phosphorylation which, in turn, activates VEGFR2, leading to an angiogenic response. Accordingly, the BMPR inhibitor dorsomorphin prevents c-Src activation and specific inhibition of c-Src significantly reduces downstream VEGFR2 phosphorylation and the angiogenic activity exerted by BMP4 in a chick embryo chorioallantoic membrane assay. Together, our data indicate that the pro-angiogenic activity exerted by BMP4 in endothelial cells is mediated by a BMPR-mediated intracellular transactivation of VEGFR2 via c-Src.
骨形态发生蛋白 4（BMP4）调节多种生物学过程，包括血管发育和血管生成。在这里，我们研究了血管内皮生长因子受体 2（VEGFR2）在介导 BMP4 的血管生成活性中的作用。BMP4 诱导内皮细胞膜上 VEGFR2 的快速重定位和磷酸化。这些作用发生在 BMP4 和/或 BMP 受体与 VEGFR2 之间没有直接相互作用的情况下。相反，BMP4 通过与 BMPRI-II 异源复合物相互作用，诱导 c-Src 磷酸化，进而激活 VEGFR2，导致血管生成反应。因此，BMPR 抑制剂 dorsomorphin 可阻止 c-Src 的激活，而 c-Src 的特异性抑制可显著降低下游 VEGFR2 的磷酸化以及 BMP4 在鸡胚绒毛尿囊膜测定中的血管生成活性。总之，我们的数据表明，BMP4 在内皮细胞中发挥的促血管生成活性是通过 BMPR 介导的 c-Src 介导的 VEGFR2 细胞内反式激活来介导的。
