Coupling of Integrin α5 to Annexin A2 by Flow Drives Endothelial Activation

Author:

Zhang Chenghu1,Zhou Ting1,Chen Zhipeng1,Yan Meng1ORCID,Li Bochuan1,Lv Huizhen12,Wang Chunjiong1,Xiang Song3ORCID,Shi Lei32,Zhu Yi1ORCID,Ai Ding12ORCID

Affiliation:

1. State Key Laboratory of Experimental Hematology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education) and Department of Physiology and Pathophysiology, Tianjin Key Laboratory of Metabolic Diseases (C.Z., T.Z., Z.C., M.Y., B.L., H.L., C.W., Y.Z., D.A.), Tianjin Medical University, China.

2. National Clinical Research Center for Blood Diseases; Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China (H.L., L.S., D.A.).

3. Department of Biochemistry and Molecular Biology (S.X., L.S.), Tianjin Medical University, China.

Abstract

Rationale: Atherosclerosis preferentially occurs at specific sites of the vasculature where endothelial cells (ECs) are exposed to disturbed blood flow. Translocation of integrin α5 to lipid rafts promotes integrin activation and ligation, which is critical for oscillatory shear stress (OSS)-induced EC activation. However, the underlying mechanism of OSS promoted integrin α5 lipid raft translocation has remained largely unknown. Objective: The objective of this study was to specify the mechanotransduction mechanism of OSS-induced integrin α5 translocation and subsequent EC activation. Methods and Results: Mass spectrometry studies identified endothelial ANXA2 (annexin A2) as a potential carrier allowing integrin α5β1 to traffic in response to OSS. Interference by siRNA of AnxA2 in ECs greatly decreased OSS-induced integrin α5β1 translocation to lipid rafts, EC activation, and monocyte adhesion. Pharmacological and genetic inhibition of PTP1B (protein tyrosine phosphatase 1B) blunted OSS-induced integrin α5β1 activation, which is dependent on Piezo1-mediated calcium influx in ECs. Furthermore, ANXA2 was identified as a direct substrate of activated PTP1B by mass spectrometry. Using bioluminescence resonance energy transfer assay, PTP1B-dephosphorylated ANXA2 at Y24 was found to lead to conformational freedom of the C-terminal core domain from the N-terminal domain of ANXA2. Immunoprecipitation assays showed that this unmasked ANXA2-C-terminal core domain specifically binds to an integrin α5 nonconserved cytoplasmic domain but not β1. Importantly, ectopic lentiviral overexpression of an ANXA2 Y24F mutant increased and shRNA against Ptp1B decreased integrin α5β1 ligation, inflammatory signaling, and progression of plaques at atheroprone sites in apolipoprotein E ( ApoE ) −/− mice. However, the antiatherosclerotic effect of Ptp1B shRNA was abolished in AnxA2 −/− ApoE −/− mice. Conclusions: Our data elucidate a novel endothelial mechanotransduction molecular mechanism linking atheroprone flow and activation of integrin α5β1, thereby identifying a class of potential therapeutic targets for atherosclerosis. Graphic Abstract: An graphic abstract is available for this article.

Funder

Ministry of Science and Technology of the People's Republic of China

NSF | National Outstanding Youth Science Fund Project of National Natural Science Foundation of China

National Natural Science Foundation of China

Natural Science Foundation of Tianjin City

China Postdoctoral Science Foundation

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine,Physiology

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