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

Research output: Contribution to journalArticle

Neah Likhite, Vikas Yadav, Eric J. Milliman, Danesh H. Sopariwala, Sabina Lorca, Nithya P. Narayana, Megha Sheth, Erin L. Reineke, Vincent Giguère, Vihang Narkar

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.

Original languageEnglish (US)
Article numbere00411-18
JournalMolecular and Cellular Biology
Volume39
Issue number5
DOIs
StatePublished - Mar 1 2019

PMID: 30602497

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Loss of estrogen-related receptor alpha facilitates angiogenesis in endothelial cells. / Likhite, Neah; Yadav, Vikas; Milliman, Eric J.; Sopariwala, Danesh H.; Lorca, Sabina; Narayana, Nithya P.; Sheth, Megha; Reineke, Erin L.; Giguère, Vincent; Narkar, Vihang.

In: Molecular and Cellular Biology, Vol. 39, No. 5, e00411-18, 01.03.2019.

Research output: Contribution to journalArticle

Harvard

Likhite, N, Yadav, V, Milliman, EJ, Sopariwala, DH, Lorca, S, Narayana, NP, Sheth, M, Reineke, EL, Giguère, V & Narkar, V 2019, 'Loss of estrogen-related receptor alpha facilitates angiogenesis in endothelial cells' Molecular and Cellular Biology, vol. 39, no. 5, e00411-18. https://doi.org/10.1128/MCB.00411-18

APA

Likhite, N., Yadav, V., Milliman, E. J., Sopariwala, D. H., Lorca, S., Narayana, N. P., ... Narkar, V. (2019). Loss of estrogen-related receptor alpha facilitates angiogenesis in endothelial cells. Molecular and Cellular Biology, 39(5), [e00411-18]. https://doi.org/10.1128/MCB.00411-18

Vancouver

Likhite N, Yadav V, Milliman EJ, Sopariwala DH, Lorca S, Narayana NP et al. Loss of estrogen-related receptor alpha facilitates angiogenesis in endothelial cells. Molecular and Cellular Biology. 2019 Mar 1;39(5). e00411-18. https://doi.org/10.1128/MCB.00411-18

Author

Likhite, Neah ; Yadav, Vikas ; Milliman, Eric J. ; Sopariwala, Danesh H. ; Lorca, Sabina ; Narayana, Nithya P. ; Sheth, Megha ; Reineke, Erin L. ; Giguère, Vincent ; Narkar, Vihang. / Loss of estrogen-related receptor alpha facilitates angiogenesis in endothelial cells. In: Molecular and Cellular Biology. 2019 ; Vol. 39, No. 5.

BibTeX

@article{7c1842643a654e6d93a921a4d8f48b62,
title = "Loss of estrogen-related receptor alpha facilitates angiogenesis in endothelial cells",
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 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.",
keywords = "Angiogenesis, Endothelial cell, Estrogen-related receptors, Nuclear receptor, Regulation of gene expression",
author = "Neah Likhite and Vikas Yadav and Milliman, {Eric J.} and Sopariwala, {Danesh H.} and Sabina Lorca and Narayana, {Nithya P.} and Megha Sheth and Reineke, {Erin L.} and Vincent Gigu{\`e}re and Vihang Narkar",
year = "2019",
month = "3",
day = "1",
doi = "10.1128/MCB.00411-18",
language = "English (US)",
volume = "39",
journal = "Molecular and Cellular Biology",
issn = "0270-7306",
publisher = "American Society for Microbiology",
number = "5",

}

RIS

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

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

UR - http://www.scopus.com/inward/record.url?scp=85062917055&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85062917055&partnerID=8YFLogxK

U2 - 10.1128/MCB.00411-18

DO - 10.1128/MCB.00411-18

M3 - Article

VL - 39

JO - Molecular and Cellular Biology

T2 - Molecular and Cellular Biology

JF - Molecular and Cellular Biology

SN - 0270-7306

IS - 5

M1 - e00411-18

ER -

ID: 47221989