| First Author | Zeng L | Year | 2013 |
| Journal | Circulation | Volume | 127 |
| Issue | 16 | Pages | 1712-22 |
| PubMed ID | 23529610 | Mgi Jnum | J:211440 |
| Mgi Id | MGI:5575452 | Doi | 10.1161/CIRCULATIONAHA.112.001337 |
| Citation | Zeng L, et al. (2013) Vascular endothelial cell growth-activated XBP1 splicing in endothelial cells is crucial for angiogenesis. Circulation 127(16):1712-22 |
| abstractText | 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/GSK3beta/beta-catenin/E2F2-dependent manner and modulated the cell size increase in a PI3K/Akt/GSK3beta/beta-catenin/E2F2-independent manner. Knockdown of XBP1 or inositol requiring enzyme 1 alpha decreased endothelial cell proliferation via suppression of Akt/GSK3beta 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. |
