VEGF-Activated XBP1 Splicing in Endothelial Cells is Crucial for Angiogenesis
Background—Vascular endothelial cell growth factor (VEGF) plays a pivotal role in angiogenesis via regulating endothelial cell (EC) proliferation. The X-box binding protein 1 (XBP1) is believed to be a signal transducer in the endoplasmic reticulum (ER) stress response. It is unknown whether there is crosstalk between VEGF signaling and XBP1 pathway.
Methods and Results—we found that VEGF induced the kinase insert domain receptor (KDR) internalization and interaction through C-terminal domain with the unspliced XBP1 and the inositol requiring enzyme 1 alpha (IRE1α) in the ER, leading to IRE1α phosphorylation and XBP1 mRNA splicing, which was abolished by siRNA-mediated knockdown of KDR. Spliced XBP1 regulated EC proliferation in a PI3K/Akt/GSK3β/β-catenin/ E2F2-dependent manner while modulated the cell size increase in a PI3K/Akt/GSK3β/β-catenin/ E2F2-independent manner. Knockdown of XBP1 or IRE1α decreased EC proliferation via suppression of Akt/GSK3β phosphorylation, β-catenin nuclear translocation and E2F2 expression. Endothelial cell-specific knockout of XBP1 (XBP1ecko) in mice retarded the retinal vasculogenesis in the first two 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.
Conclusion—These results suggest that XBP1 can function via growth factor signaling pathways to regulate endothelial proliferation and angiogenesis.
- Received January 14, 2013.
- Revision received February 22, 2013.
- Accepted February 28, 2013.