Centre for Molecular Medicine, Institute for Vascular Signalling, Goethe University, Frankfurt am Main, Germany.
German Centre of Cardiovascular Research (DZHK), Partner site Rhein-Main, Frankfurt am Main, Germany.
EMBO Rep. 2021 Feb 3;22(2):e48961. doi: 10.15252/embr.201948961. Epub 2021 Jan 29.
Endothelial tip cells are essential for VEGF-induced angiogenesis, but underlying mechanisms are elusive. The Ena/VASP protein family, consisting of EVL, VASP, and Mena, plays a pivotal role in axon guidance. Given that axonal growth cones and endothelial tip cells share many common features, from the morphological to the molecular level, we investigated the role of Ena/VASP proteins in angiogenesis. EVL and VASP, but not Mena, are expressed in endothelial cells of the postnatal mouse retina. Global deletion of EVL (but not VASP) compromises the radial sprouting of the vascular plexus in mice. Similarly, endothelial-specific EVL deletion compromises the radial sprouting of the vascular plexus and reduces the endothelial tip cell density and filopodia formation. Gene sets involved in blood vessel development and angiogenesis are down-regulated in EVL-deficient P5-retinal endothelial cells. Consistently, EVL deletion impairs VEGF-induced endothelial cell proliferation and sprouting, and reduces the internalization and phosphorylation of VEGF receptor 2 and its downstream signaling via the MAPK/ERK pathway. Together, we show that endothelial EVL regulates sprouting angiogenesis via VEGF receptor-2 internalization and signaling.
内皮细胞尖端细胞对于 VEGF 诱导的血管生成是必不可少的，但潜在的机制尚不清楚。Ena/VASP 蛋白家族，包括 EVL、VASP 和 Mena，在轴突导向中发挥着关键作用。鉴于轴突生长锥和内皮细胞尖端细胞在形态和分子水平上具有许多共同特征，我们研究了 Ena/VASP 蛋白在血管生成中的作用。EVL 和 VASP，但不是 Mena，在出生后小鼠视网膜的内皮细胞中表达。EVL 的全局缺失（但不是 VASP）会损害小鼠血管丛的放射状发芽。同样，内皮细胞特异性的 EVL 缺失会损害血管丛的放射状发芽，并降低内皮细胞尖端细胞密度和丝状伪足形成。EVL 缺陷的 P5 视网膜内皮细胞中涉及血管发育和血管生成的基因集下调。一致地，EVL 缺失会损害 VEGF 诱导的内皮细胞增殖和发芽，并通过 MAPK/ERK 途径减少 VEGF 受体 2 的内化和磷酸化及其下游信号。总之，我们表明内皮细胞 EVL 通过 VEGF 受体 2 的内化和信号转导来调节发芽血管生成。
