Propofol attenuates angiogenesis by activating endoplasmic reticulum stress to suppress TFAP2C-driven VEGFA transcription.

During anesthesia, significant hemodynamic changes often alter the vascular microenvironment and affecting endothelial cell behavior. Propofol, a commonly used intravenous anesthetic, has been widely studied for its role in tumor angiogenesis through tumor cell-derived VEGF-mediated endothelial interactions. However, its direct effects on endothelial cell-mediated angiogenesis in non-malignant diseases such as diabetic retinopathy, diabetic nephropathy, and coronary heart disease remain unclear. To address this gap, we examined the effects of propofol on VEGFA-mediated angiogenesis in vitro and in vivo. Mechanistically, propofol triggers endoplasmic reticulum stress by promoting phosphorylation of PERK and its downstream effector eIF2α, leading to suppressed translation of TFAP2C-a transcription factor critical for endothelial function. Further analysis revealed that TFAP2C directly binds to the VEGFA promoter to activate its transcription, thereby facilitating VEGFA/VEGFR2-dependent angiogenesis. Together, these findings not only broaden the understanding of propofol's pharmacological profile, but also identify TFAP2C as a novel transcriptional regulator of VEGFA, offering new perspectives for therapeutic targeting of VEGFA-mediated angiogenesis.