홍순국 (University of California, Los Angeles) | 한빛사논문 > 한빛사

한빛사논문

조회343

University of California, Los Angeles

J. Clin. Invest., May 21 2024, e175057 | https://doi.org/10.1172/JCI175057 Mechanosensitive membrane domains regulate calcium entry in arterial endothelial cells to protect against inflammation

Soon-Gook Hong^1,2, Julianne W. Ashby1, John P. Kennelly^2,3, Meigan Wu^1,2, Michelle Steel¹, Eesha Chattopadhyay¹, Rob Foreman⁴, Peter Tontonoz^2,3, Elizabeth J. Tarling^1,2, Patric Turowski⁵, Marcus Gallagher-Jones⁶ and Julia J. Mack^1,2*

¹Department of Medicine, Division of Cardiology, University of California, Los Angeles, CA, USA.

²Molecular Biology Institute, University of California, Los Angeles, CA, USA.

³Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA, USA.

⁴Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, CA, USA.

⁵UCL Institute of Ophthalmology, University of College London, London, UK.

⁶Correlated Imaging, The Rosalind Franklin Institute, Harwell Science & Innovation Campus, Didcot, UK.

^*Address correspondence: Julia J. Mack,

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.

논문정보

형식Research article
게재일2024년 05월 (BRIC 등록일 2024-05-22)
연구진국외 연구진
분야 생명과학 > 세포생물학

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