c-Src-induced vascular malformations require localised matrix degradation at focal adhesions

Author:

Essebier Patricia1ORCID,Keyser Mikaela1ORCID,Yordanov Teodor1ORCID,Hill Brittany1,Yu Alexander1,Noordstra Ivar1ORCID,Yap Alpha S.1ORCID,Stehbens Samantha J.12ORCID,Lagendijk Anne K.1ORCID,Schimmel Lilian1ORCID,Gordon Emma J.1ORCID

Affiliation:

1. Centre for Cell Biology of Chronic Disease, Institute for Molecular Bioscience, The University of Queensland, St. Lucia 1 , Brisbane, Queensland , Australia 4072

2. Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St. Lucia 2 , Brisbane, Queensland , Australia 4072

Abstract

ABSTRACT Endothelial cells lining the blood vessel wall communicate intricately with the surrounding extracellular matrix, translating mechanical cues into biochemical signals. Moreover, vessels require the capability to enzymatically degrade the matrix surrounding them, to facilitate vascular expansion. c-Src plays a key role in blood vessel growth, with its loss in the endothelium reducing vessel sprouting and focal adhesion signalling. Here, we show that constitutive activation of c-Src in endothelial cells results in rapid vascular expansion, operating independently of growth factor stimulation or fluid shear stress forces. This is driven by an increase in focal adhesion signalling and size, with enhancement of localised secretion of matrix metalloproteinases responsible for extracellular matrix remodelling. Inhibition of matrix metalloproteinase activity results in a robust rescue of the vascular expansion elicited by heightened c-Src activity. This supports the premise that moderating focal adhesion-related events and matrix degradation can counteract abnormal vascular expansion, with implications for pathologies driven by unusual vascular morphologies.

Funder

European Molecular Biology Organization

National Health and Medical Research Council of Australia and the Australian Research Council

Australian Research Council

National Health and Medical Research Council

University of Queensland

National Heart Foundation

Publisher

The Company of Biologists

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1. First person – Patricia Essebier;Journal of Cell Science;2024-07-01

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