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

Lingfang Zeng*, Qingzhong Xiao, Mei Chen, Andriana Margariti, Daniel Martin, Aleksandar Ivetic, Heping Xu, Justin Mason, Wen Wang, Gillian Cockerill, Kazutoshi Mori, Julie Yi-Shuan Li, Shu Chien, Yanhua Hu, Qingbo Xu

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

98 Citations (Scopus)

Abstract

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.)

Original languageEnglish
Pages (from-to)1712-1722
Number of pages11
JournalCirculation (Baltimore)
Volume127
Issue number16
Early online date25 Mar 2013
DOIs
Publication statusPublished - 23 Apr 2013

Keywords

  • angiogenesis
  • endothelial cells
  • ischemia
  • signal transduction
  • UNFOLDED PROTEIN RESPONSE
  • ENDOPLASMIC-RETICULUM STRESS
  • TRANSCRIPTION FACTOR ATF6
  • MESSENGER-RNA
  • PROGENITOR CELLS
  • VEIN GRAFTS
  • ER STRESS
  • PROLIFERATION
  • MICE
  • ATHEROSCLEROSIS

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