NOTCH1 is a mechanosensor in adult arteries

Julia J. Mack(University of California, Los Angeles), Thiago Mosqueiro(QB3), Brian J. Archer(University of California, Los Angeles), William M. Jones(University of California, Los Angeles), Hannah Sunshine(University of California, Los Angeles), Guido C. Faas(University of California, Los Angeles), Anaïs Briot(University of California, Los Angeles), Raquel Aragón(University of California, Los Angeles), Trent Su(University of California, Los Angeles), Milagros C. Romay(University of California, Los Angeles), Austin I. McDonald(University of California, Los Angeles), Cheng‐Hsiang Kuo(University of Chicago), Carlos O. Lizama(University of California, San Francisco), Timothy F. Lane(University of California, Los Angeles), Ann C. Zovein(University of California, San Francisco), Yun Fang(University of Chicago), Elizabeth J. Tarling(University of California, Los Angeles), Thomas Q. de Aguiar Vallim(University of California, Los Angeles), Mohamad Navab(University of California, Los Angeles), Alan M. Fogelman(University of California, Los Angeles), Louis‐S. Bouchard(University of California, Los Angeles), M. Luisa Iruela‐Arispe(University of California, Los Angeles)
Nature Communications
November 14, 2017
10.1038/s41467-017-01741-8
Cited by 306Open Access
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Abstract

Endothelial cells transduce mechanical forces from blood flow into intracellular signals required for vascular homeostasis. Here we show that endothelial NOTCH1 is responsive to shear stress, and is necessary for the maintenance of junctional integrity, cell elongation, and suppression of proliferation, phenotypes induced by laminar shear stress. NOTCH1 receptor localizes downstream of flow and canonical NOTCH signaling scales with the magnitude of fluid shear stress. Reduction of NOTCH1 destabilizes cellular junctions and triggers endothelial proliferation. NOTCH1 suppression results in changes in expression of genes involved in the regulation of intracellular calcium and proliferation, and preventing the increase of calcium signaling rescues the cell-cell junctional defects. Furthermore, loss of Notch1 in adult endothelium increases hypercholesterolemia-induced atherosclerosis in the descending aorta. We propose that NOTCH1 is atheroprotective and acts as a mechanosensor in adult arteries, where it integrates responses to laminar shear stress and regulates junctional integrity through modulation of calcium signaling.

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