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VEGF-A/Notch-Induced Podosomes Proteolyse Basement Membrane Collagen-IV during Retinal Sprouting Angiogenesis

By Pirjo Spuul, Thomas Daubon, Bettina Pitter, Florian Alonso, Isabelle Fremaux, IJsbrand Kramer, Eloi Montanez and Elisabeth Génot

Abstract

During angiogenic sprouting, endothelial tip cells emerge from existing vessels in a process that requires vascular basement membrane degradation. Here, we show that F-actin/cortactin/P-Src-based matrix-degrading microdomains called podosomes contribute to this step. In vitro, VEGF-A/Notch signaling regulates the formation of functional podosomes in endothelial cells. Using a retinal neovascularization model, we demonstrate that tip cells assemble podosomes during physiological angiogenesis in vivo. In the retina, podosomes are also part of an interconnected network that surrounds large microvessels and impinges on the underlying basement membrane. Consistently, collagen-IV is scarce in podosome areas. Moreover, Notch inhibition exacerbates podosome formation and collagen-IV loss. We propose that the localized proteolytic action of podosomes on basement membrane collagen-IV facilitates endothelial cell sprouting and anastomosis within the developing vasculature. The identification of podosomes as key components of the sprouting machinery provides another opportunity to target angiogenesis therapeutically

Topics: Medizin, ddc:610
Publisher: 'Elsevier BV'
Year: 2016
DOI identifier: 10.1016/j.celrep.2016.09.016
OAI identifier: oai:epub.ub.uni-muenchen.de:37524
Provided by: Open Access LMU
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