TY - JOUR
T1 - Loss of estrogen-related receptor alpha facilitates angiogenesis in endothelial cells
AU - Likhite, Neah
AU - Yadav, Vikas
AU - Milliman, Eric J.
AU - Sopariwala, Danesh H.
AU - Lorca, Sabina
AU - Narayana, Nithya P.
AU - Sheth, Megha
AU - Reineke, Erin L.
AU - Giguère, Vincent
AU - Narkar, Vihang
N1 - Funding Information:
This work was supported by grants from The Welch Foundation (no. L-AU-0002) and NIH/NHLBI (R01 HL129191-01) to V.N., as well as by UTHealth intramural funds. We have no financial disclosures to report. We have no conflicts of interest to declare. We thank Zhengmei Mao and the IMM Microscopy Core for assistance with imaging. We also thank Zhanguo Gao and Misha Kolonin for help with the Seahorse assay.
Publisher Copyright:
Copyright © 2019 American Society for Microbiology. All Rights Reserved.
PY - 2019/3/1
Y1 - 2019/3/1
N2 - 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 ERRα in endothelial cells (ECs), a cell type with a multifaceted role in vasculature. Of the three ERR subtypes, ECs exclusively express ERRα. Gene expression profiling of ECs lacking ERRα revealed that ERRα predominantly acts as a transcriptional repressor, targeting genes linked with angiogenesis, cell migration, and cell adhesion. ERRα-deficient ECs exhibit decreased proliferation but increased migration and tube formation. ERRα 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 ERRα knockout mice compared to that in wild-type mice. Surprisingly, ERRα is dispensable for the regulation of its classic targets, such as metabolism, mitochondrial biogenesis, and cellular respiration in the ECs. ERRα is enriched at the promoters of angiogenic, migratory, and cell adhesion genes. Further, VEGFA increased ERRα recruitment to angiogenesis-associated genes and simultaneously decreased their expression. Despite increasing its gene occupancy, proangiogenic stimuli decrease ERRα expression in ECs. Our work shows that endothelial ERRα plays a repressive role in angiogenesis and potentially fine-tunes growth factor-mediated angiogenesis.
AB - 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 ERRα in endothelial cells (ECs), a cell type with a multifaceted role in vasculature. Of the three ERR subtypes, ECs exclusively express ERRα. Gene expression profiling of ECs lacking ERRα revealed that ERRα predominantly acts as a transcriptional repressor, targeting genes linked with angiogenesis, cell migration, and cell adhesion. ERRα-deficient ECs exhibit decreased proliferation but increased migration and tube formation. ERRα 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 ERRα knockout mice compared to that in wild-type mice. Surprisingly, ERRα is dispensable for the regulation of its classic targets, such as metabolism, mitochondrial biogenesis, and cellular respiration in the ECs. ERRα is enriched at the promoters of angiogenic, migratory, and cell adhesion genes. Further, VEGFA increased ERRα recruitment to angiogenesis-associated genes and simultaneously decreased their expression. Despite increasing its gene occupancy, proangiogenic stimuli decrease ERRα expression in ECs. Our work shows that endothelial ERRα plays a repressive role in angiogenesis and potentially fine-tunes growth factor-mediated angiogenesis.
KW - Angiogenesis
KW - Endothelial cell
KW - Estrogen-related receptors
KW - Nuclear receptor
KW - Regulation of gene expression
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U2 - 10.1128/MCB.00411-18
DO - 10.1128/MCB.00411-18
M3 - Article
C2 - 30602497
AN - SCOPUS:85062917055
SN - 0270-7306
VL - 39
JO - Molecular and Cellular Biology
JF - Molecular and Cellular Biology
IS - 5
M1 - e00411-18
ER -