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Principles of Axial Polarity-Driven Vascular Patterning

Funding Agency: European Commission

Funding Programme. Horizon 2020

Call/Topic: ERC-StG-2015

Project Reference: 679368

Start Date: 2016.09.01

Duration: 60 months

Total Investment: EUR 1 618 750 (EU contribution: EUR 1 618 750)

Project Coordinator: Cláudio Areias Franco

Project Beneficiaries: Instituto de Medicina Molecular João Lobo Antunes (iMM), Portugal

This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 679368.

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The formation of a functional patterned vascular network is essential for development, tissue growth and organ physiology. Several human vascular disorders arise from the mis-patterning of blood vessels, such as arteriovenous malformations, aneurysms and diabetic retinopathy. Although blood flow is recognised as a stimulus for vascular patterning, very little is known about the molecular mechanisms that regulate endothelial cell behaviour in response to flow and promote vascular patterning.

Recently, we uncovered that endothelial cells migrate extensively in the immature vascular network, and that endothelial cells polarise against the blood flow direction. Here, we put forward the hypothesis that vascular patterning is dependent on the polarisation and migration of endothelial cells against the flow direction, in a continuous flux of cells going from low-shear stress to high-shear stress regions. We will establish new reporter mouse lines to observe and manipulate endothelial polarity in vivo in order to investigate how polarisation and coordination of endothelial cells movements are orchestrated to generate vascular patterning. We will manipulate cell polarity using mouse models to understand the importance of cell polarisation in vascular patterning. Also, using a unique zebrafish line allowing analysis of endothelial cell polarity, we will perform a screen to identify novel regulators of vascular patterning. Finally, we will explore the hypothesis that defective flow-dependent endothelial polarisation underlies arteriovenous malformations using two genetic models.