Vascular Endothelial Cell Growth-Activated XBP1 Splicing in Endothelial Cells Is Crucial for Angiogenesis

Article

关键词: UNFOLDED PROTEIN RESPONSE;    TRANSCRIPTION FACTOR ATF6;    MESSENGER-RNA;    PROGENITOR CELLS;    VEIN GRAFTS;    ER STRESS;    PROLIFERATION;    ATHEROSCLEROSIS;    DIFFERENTIATION;    PXBP1(U);   

DOI  :  10.1161/CIRCULATIONAHA.112.001337

来源: SCIE

【 摘 要 】

Background-Vascular endothelial cell growth factor plays a pivotal role in angiogenesis via regulating endothelial cell proliferation. The X-box binding protein 1 (XBP1) is believed to be a signal transducer in the endoplasmic reticulum stress response. It is unknown whether there is crosstalk between vascular endothelial cell growth factor signaling and XBP1 pathway. Methods and Results-We found that vascular endothelial cell growth factor induced the kinase insert domain receptor internalization and interaction through C-terminal domain with the unspliced XBP1 and the inositol requiring enzyme 1 alpha in the endoplasmic reticulum, leading to inositol requiring enzyme 1 alpha phosphorylation and XBP1 mRNA splicing, which was abolished by siRNA-mediated knockdown of kinase insert domain receptor. Spliced XBP1 regulated endothelial cell proliferation in a PI3K/Akt/GSK3 beta/beta-catenin/E2F2-dependent manner and modulated the cell size increase in a PI3K/Akt/GSK3 beta/beta-catenin/E2F2-independent manner. Knockdown of XBP1 or inositol requiring enzyme 1 alpha decreased endothelial cell proliferation via suppression of Akt/GSK3 beta phosphorylation, beta-catenin nuclear translocation, and E2F2 expression. Endothelial cell-specific knockout of XBP1 (XBP1ecko) in mice retarded the retinal vasculogenesis in the first 2 postnatal weeks and impaired the angiogenesis triggered by ischemia. Reconstitution of XBP1 by Ad-XBP1s gene transfer significantly improved angiogenesis in ischemic tissue in XBP1ecko mice. Transplantation of bone marrow from wild-type o XBP1ecko mice could also slightly improve the foot blood reperfusion in ischemic XBP1ecko mice. Conclusions-These results suggest that XBP1 can function via growth factor signaling pathways to regulate endothelial proliferation and angiogenesis. (Circulation. 2013; 127:1712-1722.)

【 授权许可】

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