Endothelial Cell Migration in Three Dimensions

National Heart, Lung, And Blood Institute

Investigators

Abstract

Project 1;Myosin II mediates local cortical tension to guide endothelial cell branching[unreadable] morphogenesis and migration in 3D.[unreadable] Personell: Robert Fischer[unreadable] [unreadable] Angiogenesis is a critical process in both development and disease, where it represents[unreadable] a prime target for therapeutic intervention. Since new blood vessels are directed[unreadable] to tissues with metabolic demands, a key feature of angiogenesis is directional control of[unreadable] endothelial cell (EC) morphogenesis and movement. During angiogenic sprouting,[unreadable] single endothelial tip cells directionally branch from existing vessels in response to[unreadable] biochemical cues such as VEGF and migrate and invade the surrounding extracellular[unreadable] matrix (ECM) in a process that requires ECM remodeling by matrix metalloproteases[unreadable] (MMPs). This is followed by EC proliferation and tubulation to establish a new[unreadable] vessel. Tip cell branching is mediated by directional protrusion at the subcellular level. Here we sought to understand how directional protrusion is locally regulated to guide[unreadable] EC branching morphogenesis. We developed an in vitro 3D EC model system that[unreadable] faithfully mimicks EC morphodynamics in angiogenesis in living zebrafish. We[unreadable] demonstrate that ECM stiffness and ROCK-mediated myosin II activity inhibit EC branch[unreadable] initiation. Myosin II is localized at the EC cortex, from which it is partially released under[unreadable] conditions that promote EC branching. Local depletion of cortical myosin II precedes[unreadable] branch initiation, and initiation can be induced by local inhibition of myosin II activity.[unreadable] Thus, local downregulation of myosin II cortical contraction allows pseudopod initiation[unreadable] to regulate EC branching and hence guide directional migration and angiogenesis.[unreadable] [unreadable] This work was performed in collaboration with Bob Adelstein and Xuefei Ma (NHLBI) and Margaret Gardel (U Chicago) and has been submitted for publication.[unreadable] [unreadable] Project 2: Development of algorithms for tracking cell morphodynamics in three dimensions.[unreadable] [unreadable] Personell: Bob Fischer[unreadable] In collaboration with Gaudenz Danuser and Sam Ching at Scripps and performed at MBL at Woods Hole. This is ongoing.