| First Author | Likhite N | Year | 2019 |
| Journal | Mol Cell Biol | Volume | 39 |
| Issue | 5 | PubMed ID | 30602497 |
| Mgi Jnum | J:291313 | Mgi Id | MGI:6446465 |
| Doi | 10.1128/MCB.00411-18 | Citation | Likhite N, et al. (2019) Loss of Estrogen-Related Receptor Alpha Facilitates Angiogenesis in Endothelial Cells. Mol Cell Biol 39(5) |
| abstractText | 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 ERRalpha in endothelial cells (ECs), a cell type with a multifaceted role in vasculature. Of the three ERR subtypes, ECs exclusively express ERRalpha. Gene expression profiling of ECs lacking ERRalpha revealed that ERRalpha predominantly acts as a transcriptional repressor, targeting genes linked with angiogenesis, cell migration, and cell adhesion. ERRalpha-deficient ECs exhibit decreased proliferation but increased migration and tube formation. ERRalpha 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 ERRalpha knockout mice compared to that in wild-type mice. Surprisingly, ERRalpha is dispensable for the regulation of its classic targets, such as metabolism, mitochondrial biogenesis, and cellular respiration in the ECs. ERRalpha is enriched at the promoters of angiogenic, migratory, and cell adhesion genes. Further, VEGFA increased ERRalpha recruitment to angiogenesis-associated genes and simultaneously decreased their expression. Despite increasing its gene occupancy, proangiogenic stimuli decrease ERRalpha expression in ECs. Our work shows that endothelial ERRalpha plays a repressive role in angiogenesis and potentially fine-tunes growth factor-mediated angiogenesis. |
