Transcriptional Regulation of VEGF-A by the Unfolded Protein Response Pathway

Background: Angiogenesis is crucial to many physiological and pathological processes including development and cancer cell survival. Vascular endothelial growth factor-A (VEGFA) is the predominant mediator of angiogenesis in the VEGF family. During development, adverse environmental conditions like nutrient deprivation, hypoxia and increased protein secretion occur. IRE1 alpha, PERK, and ATF6 alpha, master regulators of the unfolded protein response (UPR), are activated under these conditions and are proposed to have a role in mediating angiogenesis. Principal Findings: Here we show that IRE1 alpha, PERK, and ATF6 alpha powerfully regulate VEGFA mRNA expression under various stress conditions. In Ire1 alpha(-/-) and Perk(-/-) mouse embryonic fibroblasts and ATF6 alpha-knockdown HepG2 cells, induction of VEGFA mRNA by endoplasmic reticulum stress is attenuated as compared to control cells. Embryonic lethality of Ire1 alpha(-/-) mice is due to the lack of VEGFA induction in labyrinthine trophoblast cells of the developing placenta. Rescue of IRE1 alpha and PERK in Ire1 alpha(-/-) and Perk(-/-) cells respectively, prevents VEGFA mRNA attenuation. We further report that the induction of VEGFA by IRE1 alpha, PERK and ATF6 involves activation of transcription factors, spliced-XBP-1, ATF4 and cleaved ATF6 respectively. Conclusions/Significance: Our results reveal that the IRE1 alpha-XBP-1, PERK-ATF4, and ATF6a pathways constitute novel upstream regulatory pathways of angiogenesis by modulating VEGF transcription. Activation of these pathways helps the rapidly growing cells to obtain sufficient nutrients and growth factors for their survival under the prevailing hostile environmental conditions. These results establish an important role of the UPR in angiogenesis.