Loss of estrogen-related receptor alpha facilitates angiogenesis in endothelial cells.

Estrogen-related receptors (ERRs) have emerged as major metabolic regulators in various tissues. However, their expression and function in the vasculature remains unknown. Here, we report the transcriptional program and cellular function of ERR alpha in endothelial cells (ECs), a cell type with a multifaceted role in vasculature. Of the three ERR subtypes, ECs exclusively express ERR alpha. Gene expression profiling of ECs lacking ERR alpha revealed that ERR alpha predominantly acts as a transcriptional repressor, targeting genes linked with angiogenesis, cell migration, and cell adhesion. ERR alpha-deficient ECs exhibit decreased proliferation but increased migration and tube formation. ERR alpha depletion increased basal as well as vascular endothelial growth factor A (VEGFA) and ANG1/2-stimulated angiogenic sprouting in endothelial spheroids. Moreover, retinal angiogenesis is enhanced in ERR alpha knockout mice compared to that in wild-type mice. Surprisingly, ERR alpha is dispensable for the regulation of its classic targets, such as metabolism, mitochondrial biogenesis, and cellular respiration in the ECs. ERR alpha is enriched at the promoters of angiogenic, migratory, and cell adhesion genes. Further, VEGFA increased ERR alpha recruitment to angiogenesis-associated genes and simultaneously decreased their expression. Despite increasing its gene occupancy, proangiogenic stimuli decrease ERR alpha expression in ECs. Our work shows that endothelial ERR alpha plays a repressive role in angiogenesis and potentially fine-tunes growth factor-mediated angiogenesis.