1. Academic Validation
  2. Mechanosensitive membrane domains regulate calcium entry in arterial endothelial cells to protect against inflammation

Mechanosensitive membrane domains regulate calcium entry in arterial endothelial cells to protect against inflammation

  • J Clin Invest. 2024 May 21:e175057. doi: 10.1172/JCI175057.
Soon-Gook Hong 1 Julianne W Ashby 1 John P Kennelly 2 Meigan Wu 1 Michelle Steel 1 Eesha Chattopadhyay 1 Rob Foreman 3 Peter Tontonoz 2 Elizabeth J Tarling 1 Patric Turowski 4 Marcus Gallagher-Jones 5 Julia J Mack 1
Affiliations

Affiliations

  • 1 Department of Medicine, Division of Cardiology, David Geffen School of Medicine, UCLA, Los Angeles, United States of America.
  • 2 Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, United States of America.
  • 3 Institute for Quantitative and Computational Biosciences, UCLA, Los Angeles, United States of America.
  • 4 UCL Institute of Ophthalmology, University College London, London, United Kingdom.
  • 5 Correlated Imaging, The Rosalind Franklin Institute, Didcot, United Kingdom.
Abstract

Endothelial cells (ECs) in the descending aorta are exposed to high laminar shear stress, and this supports an anti-inflammatory phenotype. High laminar shear stress also induces flow-aligned cell elongation and front-rear polarity, but whether these are required for the anti-inflammatory phenotype is unclear. Here, we showed that Caveolin-1-rich microdomains polarize to the downstream end of ECs that are exposed to continuous high laminar flow. These microdomains were characterized by high membrane rigidity, filamentous actin (F-actin), and raft-associated lipids. Transient receptor potential vanilloid-type 4 (TRPV4) ion channels were ubiquitously expressed on the plasma membrane but mediated localized Ca2+ entry only at these microdomains where they physically interacted with clustered Caveolin-1. These focal Ca2+ bursts activated endothelial nitric oxide synthase (eNOS) within the confines of these domains. Importantly, we found that signaling at these domains required both cell body elongation and sustained flow. Finally, TRPV4 signaling at these domains was necessary and sufficient to suppress inflammatory gene expression, and exogenous activation of TRPV4 channels ameliorated the inflammatory response to stimuli both in vitro and in vivo. Our work revealed a polarized mechanosensitive signaling hub in arterial ECs that dampens inflammatory gene expression and promotes cell resilience.

Keywords

Calcium signaling; Cell biology; Endothelial cells; Vascular biology.

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