EVL regulates VEGF receptor-2 internalization and signaling in developmental angiogenesis.


Zink J(1)(2), Frye M(3), Frömel T(1)(2), Carlantoni C(3), John D(2)(4), Schreier D(3), Weigert A(5), Laban H(6), Salinas G(7), Stingl H(1)(2), Günther L(1)(2), Popp R(1)(2), Hu J(1)(2), Vanhollebeke B(8), Schmidt H(9), Acker-Palmer A(10), Renné T(3), Fleming I(1)(2), Benz PM(1)(2).
Author information:
(1)Centre for Molecular Medicine, Institute for Vascular Signalling, Goethe University, Frankfurt am Main, Germany.
(2)German Centre of Cardiovascular Research
(DZHK), Partner site Rhein-Main, Frankfurt am Main, Germany.
(3)Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
(4)Insitute for Cardiovascular Regeneration, Goethe University, Frankfurt am Main, Germany.
(5)Institute of Biochemistry I-Pathobiochemistry, Faculty of Medicine, Goethe-University, Frankfurt am Main, Germany.
(6)Department of Cardiovascular Physiology, Institute of Physiology and Pathophysiology, Heidelberg University, Heidelberg, Germany.
(7)NGS-Integrative Genomics Core Unit
(NIG), Institute of Human Genetics, University Medical Center Göttingen
(UMG), Göttingen, Germany.
(8)Laboratory of Neurovascular Signaling, ULB Neuroscience Institute Department of Molecular Biology, University of Brussels, Walloon Excellence in Life Sciences and Biotechnology
(WELBIO), Brussels, Belgium.
(9)Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany.
(10)Institute of Cell Biology and Neuroscience and Buchmann Institute for Molecular Life Sciences, Goethe University, Frankfurt am Main, Germany.


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.