XBP1 regulates endothelial growth and angiogenesis in ischemic tissues

Research output: Contribution to journalMeeting abstractpeer-review


Background: The X-box binding protein 1 (XBP1) is believed to be a signal transducer in the endoplasmic reticulum stress response, but little is known about its pathophysiological functions in the vasculature.

Methods and results: Targeting of XBP1 gene was performed by introducing LoxP sites in promoter region and intron 2. Crossbreeding XBP1loxP/loxP mice with CAG-Cre and Tie2-Cre mice deletes the exons 1 and 2, giving rise to global and endothelial conditional knockout mice, respectively. Global knockout of XBP1 caused embryonic lethality. In such mouse embryos, the blood vessel formation was significantly reduced partially due to a diminished number of CD31+ and Flk1+ endothelial cells. In vitro culture of whole embryonic cells, the XBP1-null cells grew significantly slower and lost response to VEGF stimulation. The endothelial conditional knockout mice could survive, but the angiogenesis and reperfusion of blood flow in hindlimb ischemic model were significantly impaired. Knockdown of XBP1 or the inositol requiring enzyme 1 (IRE1α) attenuated VEGF-induced endothelial proliferation and tube formation in vitro. Transient activation of XBP1 splicing increased β-catenin nuclear translocation and Rb nuclear export, leading to E2F2 up-regulation and cell growth. VEGF transiently activated IRE1α phosphorylation and XBP1 mRNA splicing through interaction between VEGF receptor 2 and IRE1α. The C-terminal domain of VEGF receptor 2 and the kinase domain of IRE1α were responsible for the interaction.

Conclusion: This study demonstrates for the first time that XBP1 is crucial in angiogenesis via VEGR receptor/IRE1 interaction. Fine tuning XBP1 splicing may provide a novel therapeutic strategy to intervene vascular disease.
Original languageEnglish
Pages (from-to)309-309
Number of pages1
Issue number5-6
Publication statusPublished - May 2012


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