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Mol Cell Biol. 2019 Jan 2. pii: MCB.00411-18. doi: 10.1128/MCB.00411-18. [Epub ahead of print]

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

Author information

1
Metabolic and Degenerative Diseases, Institute of Molecular Medicine, The University of Texas McGovern Medical School, Houston, TX, USA.
2
BERG LLC, Framingham, MA, USA.
3
Department of Biochemistry and Cell Biology, Rice University, Houston, TX, USA.
4
Center for Bioenergetics, Houston Methodist Research Institute, Houston, TX.
5
Department of Biochemistry, Medicine and Oncology, Faculty of Medicine, Goodman Cancer Research Centre, McGill University, Montréal, Canada.
6
Metabolic and Degenerative Diseases, Institute of Molecular Medicine, The University of Texas McGovern Medical School, Houston, TX, USA. Vihang.a.narkar@uth.tmc.edu.
7
Integrative Biology and Pharmacology, The University of Texas McGovern Medical School, Houston, TX, USA.
8
Graduate School of Biomedical Sciences at The University of Texas Health Science Center, Houston, TX, USA.

Abstract

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 multi-faceted 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, VEGFA and ANG1/2 stimulated angiogenic sprouting in endothelial spheroids. Moreover, retinal angiogenesis is enhanced in ERRα knockout mice compared to 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, pro-angiogenic 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.IMPORTANCE Impaired angiogenesis, the process of blood vessel formation, is central to various diseases including peripheral vascular disease, retinopathy, nephropathy, cardiac ischemia and cancer. While few angiogenic regulators have been described, full breadth of the cellular and molecular pathways that regulate this phenomenon are far from clear. Fundamental discoveries related to angiogenesis regulation could lead to new drugs that normalize blood vessels in the aforementioned diseases. Using a cell and molecular biology approach, our work highlights a gene regulator called ERRα in endothelial cells (the building blocks of the vasculature), which plays a role in limiting angiogenic activation by controlling endothelial gene expression. It can be envisioned that future pre-clinical and pharmaco/physiological studies could lead to advancement of ERRα as a therapeutic regulator of angiogenesis in vascular-linked diseases.

PMID:
30602497
DOI:
10.1128/MCB.00411-18

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