Journal Article

Polarized actin and VE-cadherin dynamics regulate junctional remodelling and cell migration during sprouting angiogenesis

Seebach, Jochen, Montanez, Eloi, Werner, Ann-Cathrin, Sixta, Tomas, März, Sigrid, Ehling, Manuel, Flach, Boris, Cao, Jiahui, Raz, Erez, Pitulescu, Mara E., Tarbashevich, Katsiaryna, Adams, Ralf H., Schnittler, Hans

2017

Overview

VEGFR-2/Notch signalling regulates angiogenesis in part by driving the remodelling of endothelial cell junctions and by inducing cell migration. Here, we show that VEGF-induced polarized cell elongation increases cell perimeter and decreases the relative VE-cadherin concentration at junctions, triggering polarized formation of actin-driven junction-associated intermittent lamellipodia (JAIL) under control of the WASP/WAVE/ARP2/3 complex. JAIL allow formation of new VE-cadherin adhesion sites that are critical for cell migration and monolayer integrity. Whereas at the leading edge of the cell, large JAIL drive cell migration with supportive contraction, lateral junctions show small JAIL that allow relative cell movement. VEGFR-2 activation initiates cell elongation through dephosphorylation of junctional myosin light chain II, which leads to a local loss of tension to induce JAIL-mediated junctional remodelling. These events require both microtubules and polarized Rac activity. Together, we propose a model where polarized JAIL formation drives directed cell migration and junctional remodelling during sprouting angiogenesis. The formation of new blood vessels requires both polarized cell migration and coordinated control of endothelial cell contacts. Here, Cao and colleagues describe at the sub-cellular level the cytoskeletal and cell junction dynamics regulating these processes upon VEGF-induced cell elongation.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/136/16 / 631/80/79/2028 / 631/80/84 / Actin / Actin-Related Protein 2 - metabolism / Actin-Related Protein 2-3 Complex - metabolism / Actin-Related Protein 3 - metabolism / Actins - drug effects / Actins - metabolism / Angiogenesis / Antigens, CD - drug effects / Antigens, CD - metabolism / Cadherins / Cadherins - drug effects / Cadherins - metabolism / Cardiac Myosins - metabolism / Cell activation / Cell Adhesion / Cell adhesion & migration / Cell junctions / Cell migration / Cell Movement - drug effects / Cell Movement - physiology / Cell Polarity - drug effects / Cell Polarity - physiology / Contraction / Dephosphorylation / Elongation / Endothelial cells / Endothelial Cells - drug effects / Endothelial Cells - metabolism / Endothelial Cells - physiology / Endothelium, Vascular / Human Umbilical Vein Endothelial Cells / Humanities and Social Sciences / Humans / Intercellular Junctions - drug effects / Intercellular Junctions - metabolism / Lamellipodia / Microtubules / Microtubules - drug effects / Microtubules - metabolism / Models, Cardiovascular / multidisciplinary / Myosin / Myosin Light Chains - metabolism / Neovascularization, Physiologic - drug effects / Neovascularization, Physiologic - physiology / Notch protein / Prisons / Pseudopodia / Pseudopodia - drug effects / Pseudopodia - metabolism / Pseudopodia - physiology / rac GTP-Binding Proteins - metabolism / Science / Science (multidisciplinary) / Signal Transduction / Signaling / Vascular endothelial growth factor / Vascular Endothelial Growth Factor A - metabolism / Vascular Endothelial Growth Factor A - pharmacology / Vascular Endothelial Growth Factor Receptor-2 - metabolism / Vascular endothelial growth factor receptors / Vascular Remodeling / Wiskott-Aldrich Syndrome Protein - metabolism / Wiskott-Aldrich Syndrome Protein Family - metabolism