JOURNAL ARTICLE

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

Chenghu Zhang, Ting Zhou, Zhipeng Chen, Meng Yan, Bochuan Li, Huizhen Lv, Chunjiong Wang, Song Xiang, Lei Shi, Yi Zhu, Ding Ai
Circulation Research 2020 July 16
32673515
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 Annexin A2 (ANXA2) 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 protein tyrosine phosphatase 1B (PTP1B) 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 (CTD) from the N-terminal domain of ANXA2. Immunoprecipitation assays showed that this unmasked ANXA2-CTD specifically binds to an integrin α5 non-conserved cytoplasmic domain but not β1. Importantly, ectopic lentiviral overexpression of an ANXA2Y24F mutant increased and shRNA against Ptp1B decreased integrin α5β1 ligation, inflammatory signaling and progression of plaques at atheroprone sites in apoproteinE ( ApoE)-/- mice. However, the anti-atherosclerotic effect of Ptp1B shRNA was abolished in AnxA2-/- ApoE-/- mice. Conclusions: Our data elucidate a novel endothelial mechanotransduction molecular mechanism linking athero-prone flow and activation of integrin α5β1, thereby identifying a class of potential therapeutic targets for atherosclerosis.

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