VEGF is the main regulator of blood vessel formation and a key factor in angiogenic diseases such as cancer. Its receptor VEGFR2 drives endothelial cell proliferation, migration, and survival through pathways involving PLCγ–MAPK/ERK and PI3K/AKT.

cDNA microarray analysis in HUVECs revealed that VEGF upregulates HERPUD1 and DNAJB9, two ER stress–related genes (Bellou et al., 2009). These are transcriptional targets of the unfolded protein response (UPR), triggered by accumulation of misfolded proteins and mediated by IRE1α, ATF6, and PERK.

We have shown that VEGF activates the UPR mediators IRE1α, ATF6, and PERK in endothelial cells (ECs) through PLCγ signaling, a previously unknown function of this pathway. The effect is mediated via the mTORC1 complex, which connects VEGF signaling to UPR sensors located on the ER. This activation occurs independently of unfolded protein accumulation, indicating a physiological, non-stress UPR mechanism.