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Molecular mechanisms regulating endothelial cell axial polarity during vascular morphogenesis
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The establishment of a functional patterned vascular network is crucial for development, tissue growth and homeostasis. The mis-patterning or dysfunction of this network is associated with cancer, stroke and arteriovenous malformations. The formation of a functional vascular network requires two distinct processes – formation of primitive vascular plexuses through sprouting angiogenesis; and vascular remodelling, the reorganization of primitive plexuses into a hierarchical network of arteries, capillaries and veins. During sprouting angiogenesis endothelial cells polarise and migrate towards sources of VEGF while upon vascular remodelling, they polarise and migrate against the blood flow direction. Nevertheless, the molecular mechanisms regulating migration and polarisation during sprouting and vascular remodelling are poorly understood.
Here, we investigate the mechanisms of polarisation and migration during sprouting angiogenesis by unravelling the role of Arp2/3 complex in vascular morphogenesis, using a combination of in vitro approaches with the power of mouse genetics. We show that Arp2/3 is crucial for endothelial cell migration, for the establishment of cellular protrusions and that its depletion drastically affects vascular morphogenesis during development and tumour angiogenesis.
At the same time, we show that blood flow and VEGF interact to orchestrate patterns of endothelial cell polarity at the network-level. We demonstrate that this interaction defines the transition between two distinct morphogenic events, vascular sprouting and vascular remodelling. Accordingly, manipulation of VEGF gradients or blood flow in vivo compromises normal polarity patterns, resulting in delayed or premature remodelling of blood vessels. At the molecular level, we show that mechanotransduction at adherens junctions is key for VEGF-induced polarisation and negatively regulates flow-dependent collective polarisation. Specifically, we propose that vinculin recruitment is key for mechanotransduction and the establishment of a transition zone. In addition, we generated a polarity reporter mouse with endothelial cell nuclei and Golgi labelled that will enable the study the dynamics of endothelial cell polarisation downstream of VEGF and blood flow in development, homeostasis and disease.
Given the physiological relevance of vascular patterning in health and disease, our approach will give insights in defining the cellular and molecular principles involved in vascular patterning.
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Endothelial cell polarity Blood flow VEGF Arp2/3 GNrep Polaridade células endoteliais Fluxo sanguíneo Teses de doutoramento - 2019