Matrix mechanotransduction mediated by thrombospondin-1/integrin/YAP in the vascular remodeling

Author:

Yamashiro YoshitoORCID,Thang Bui QuocORCID,Ramirez Karina,Shin Seung Jae,Kohata Tomohiro,Ohata Shigeaki,Nguyen Tram Anh Vu,Ohtsuki Sumio,Nagayama Kazuaki,Yanagisawa HiromiORCID

Abstract

The extracellular matrix (ECM) initiates mechanical cues that activate intracellular signaling through matrix–cell interactions. In blood vessels, additional mechanical cues derived from the pulsatile blood flow and pressure play a pivotal role in homeostasis and disease development. Currently, the nature of the cues from the ECM and their interaction with the mechanical microenvironment in large blood vessels to maintain the integrity of the vessel wall are not fully understood. Here, we identified the matricellular protein thrombospondin-1 (Thbs1) as an extracellular mediator of matrix mechanotransduction that acts via integrin αvβ1 to establish focal adhesions and promotes nuclear shuttling of Yes-associated protein (YAP) in response to high strain of cyclic stretch. Thbs1-mediated YAP activation depends on the small GTPase Rap2 and Hippo pathway and is not influenced by alteration of actin fibers. Deletion of Thbs1 in mice inhibited Thbs1/integrin β1/YAP signaling, leading to maladaptive remodeling of the aorta in response to pressure overload and inhibition of neointima formation upon carotid artery ligation, exerting context-dependent effects on the vessel wall. We thus propose a mechanism of matrix mechanotransduction centered on Thbs1, connecting mechanical stimuli to YAP signaling during vascular remodeling in vivo.

Funder

Grant-in Aid for Young Scientists

Japan Heart Foundation Research Grant

The Inamori Foundation

Japan Foundation for Applied Enzymology

Takeda Science Foundation

MSD Life Science Foundation

Uehara Memorial Foundation

Japan Heart Foundation Dr. Hiroshi Irisawa & Dr. Aya Irisawa Memorial Research Grant

Mext KAKENHI

The Naito Foundation

Astellas Foundation for Research on Metabolic Disorders

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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