Abstract
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.
Highlights
VEGFR-2/Notch signalling regulates angiogenesis in part by driving the remodelling of endothelial cell junctions and by inducing cell migration
VE-cadherin and actin dynamics at endothelial cells (ECs) junctions are upregulated in cells with increased cell junction length via junction-associated intermittent lamellipodia (JAIL) formation, which is activated by a reduced relative VE-cadherin concentration (Rel-VEcad-C) at extended cell junctions, the total amount of VE-cadherin remains unchanged as demonstrated in human umbilical vein endothelial cell (HUVEC) cultures[8]
Suggesting that a similar mechanism plays a role during angiogenesis, we found in VE-cadherin-labelled P6 mice retinas an increased EC junction length at the angiogenic front compared with those in the vein or in the perivenous capillaries (Fig. 1a, b)
Summary
VEGFR-2/Notch signalling regulates angiogenesis in part by driving the remodelling of endothelial cell junctions and by inducing cell migration. These data indicate that an appropriate VE-cadherin concentration at cell junctions is critical for proper angiogenesis Despite these insights, increasing vessel size and lumen formation by stalk cells increases the number of cell contacts by which a particular cell connects to several other cells, including the tip cell/stalk cell interaction, e.g., during interconversion. A structure that gave some insight into this aspect was described in a recent cell culture study, demonstrating that local reduction of VE-cadherin at particular endothelial junction sites initiates the formation of actin-driven plasma membrane protrusions. Due to their transient, spatiotemporally restricted and highly dynamic features, these structures were termed junction-associated intermittent lamellipodia (JAIL)[8]. On the basis of the results presented here, we were able to develop a model of cell junction dynamics for VEGFR2/Notchmediated polar cell migration during angiogenesis that includes contraction/relaxation mechanisms and interdependent dynamics of microtubules, VE-cadherin and actin
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