S-nitrosoglutathione reductase (GSNOR) enhances vasculogenesis by mesenchymal stem cells

Samirah A. Gomes, Erika B. Rangel, Courtney Premer, Raul A. Dulce, Yenong Cao, Victoria Florea, Wayne Balkan, Claudia O. Rodrigues, Andrew V. Schally, Joshua M. Hare

Research output: Contribution to journalArticle

Abstract

Although nitric oxide (NO) signaling promotes differentiation and maturation of endothelial progenitor cells, its role in the differentiation of mesenchymal stem cells (MSCs) into endothelial cells remains controversial. We tested the role of NO signaling in MSCs derived from WT mice and mice homozygous for a deletion of S-nitrosoglutathione reductase (GSNOR-/-), a denitrosylase that regulates S-nitrosylation. GSNOR-/- MSCs exhibited markedly diminished capacity for vasculogenesis in an in vitro Matrigel tube-forming assay and in vivo relative to WT MSCs. This decrease was associated with down-regulation of the PDGF receptorα (PDGFRα) in GSNOR -/- MSCs, a receptor essential for VEGF-A action in MSCs. Pharmacologic inhibition of NO synthase with L-NG-nitroarginine methyl ester (L-NAME) and stimulation of growth hormone-releasing hormone receptor (GHRHR) with GHRH agonists augmented VEGF-A production and normalized tube formation in GSNOR-/- MSCs, whereas NO donors or PDGFR antagonist reduced tube formation ∼50% by murine and human MSCs. The antagonist also blocked the rescue of tube formation in GSNOR-/- MSCs by L-NAME or the GHRH agonists JI-38, MR-409, and MR-356. Therefore, GSNOR -/- MSCs have a deficient capacity for endothelial differentiation due to downregulation of PDGFRα related to NO/GSNOR imbalance. These findings unravel important aspects of modulation of MSCs by VEGF-A activation of the PDGFR and illustrate a paradoxical inhibitory role of S-nitrosylation signaling in MSC vasculogenesis. Accordingly, disease states characterized by NO deficiency may trigger MSC-mediated vasculogenesis. These findings have important implications for therapeutic application of GHRH agonists to ischemic disorders.

Original languageEnglish (US)
Pages (from-to)2834-2839
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number8
DOIs
StatePublished - Feb 19 2013
Externally publishedYes

Fingerprint

glutathione-independent formaldehyde dehydrogenase
Mesenchymal Stromal Cells
Platelet-Derived Growth Factor Receptors
Nitric Oxide
Vascular Endothelial Growth Factor A
NG-Nitroarginine Methyl Ester
Down-Regulation

Keywords

  • Angiogenesis
  • Nitroso-redox imbalance

ASJC Scopus subject areas

  • General

Cite this

S-nitrosoglutathione reductase (GSNOR) enhances vasculogenesis by mesenchymal stem cells. / Gomes, Samirah A.; Rangel, Erika B.; Premer, Courtney; Dulce, Raul A.; Cao, Yenong; Florea, Victoria; Balkan, Wayne; Rodrigues, Claudia O.; Schally, Andrew V.; Hare, Joshua M.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 110, No. 8, 19.02.2013, p. 2834-2839.

Research output: Contribution to journalArticle

Gomes, SA, Rangel, EB, Premer, C, Dulce, RA, Cao, Y, Florea, V, Balkan, W, Rodrigues, CO, Schally, AV & Hare, JM 2013, 'S-nitrosoglutathione reductase (GSNOR) enhances vasculogenesis by mesenchymal stem cells', Proceedings of the National Academy of Sciences of the United States of America, vol. 110, no. 8, pp. 2834-2839. https://doi.org/10.1073/pnas.1220185110
Gomes, Samirah A. ; Rangel, Erika B. ; Premer, Courtney ; Dulce, Raul A. ; Cao, Yenong ; Florea, Victoria ; Balkan, Wayne ; Rodrigues, Claudia O. ; Schally, Andrew V. ; Hare, Joshua M. / S-nitrosoglutathione reductase (GSNOR) enhances vasculogenesis by mesenchymal stem cells. In: Proceedings of the National Academy of Sciences of the United States of America. 2013 ; Vol. 110, No. 8. pp. 2834-2839.
@article{808300a296a04f0f9f3863afddbc3dc0,
title = "S-nitrosoglutathione reductase (GSNOR) enhances vasculogenesis by mesenchymal stem cells",
abstract = "Although nitric oxide (NO) signaling promotes differentiation and maturation of endothelial progenitor cells, its role in the differentiation of mesenchymal stem cells (MSCs) into endothelial cells remains controversial. We tested the role of NO signaling in MSCs derived from WT mice and mice homozygous for a deletion of S-nitrosoglutathione reductase (GSNOR-/-), a denitrosylase that regulates S-nitrosylation. GSNOR-/- MSCs exhibited markedly diminished capacity for vasculogenesis in an in vitro Matrigel tube-forming assay and in vivo relative to WT MSCs. This decrease was associated with down-regulation of the PDGF receptorα (PDGFRα) in GSNOR -/- MSCs, a receptor essential for VEGF-A action in MSCs. Pharmacologic inhibition of NO synthase with L-NG-nitroarginine methyl ester (L-NAME) and stimulation of growth hormone-releasing hormone receptor (GHRHR) with GHRH agonists augmented VEGF-A production and normalized tube formation in GSNOR-/- MSCs, whereas NO donors or PDGFR antagonist reduced tube formation ∼50{\%} by murine and human MSCs. The antagonist also blocked the rescue of tube formation in GSNOR-/- MSCs by L-NAME or the GHRH agonists JI-38, MR-409, and MR-356. Therefore, GSNOR -/- MSCs have a deficient capacity for endothelial differentiation due to downregulation of PDGFRα related to NO/GSNOR imbalance. These findings unravel important aspects of modulation of MSCs by VEGF-A activation of the PDGFR and illustrate a paradoxical inhibitory role of S-nitrosylation signaling in MSC vasculogenesis. Accordingly, disease states characterized by NO deficiency may trigger MSC-mediated vasculogenesis. These findings have important implications for therapeutic application of GHRH agonists to ischemic disorders.",
keywords = "Angiogenesis, Nitroso-redox imbalance",
author = "Gomes, {Samirah A.} and Rangel, {Erika B.} and Courtney Premer and Dulce, {Raul A.} and Yenong Cao and Victoria Florea and Wayne Balkan and Rodrigues, {Claudia O.} and Schally, {Andrew V.} and Hare, {Joshua M.}",
year = "2013",
month = "2",
day = "19",
doi = "10.1073/pnas.1220185110",
language = "English (US)",
volume = "110",
pages = "2834--2839",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "8",

}

TY - JOUR

T1 - S-nitrosoglutathione reductase (GSNOR) enhances vasculogenesis by mesenchymal stem cells

AU - Gomes, Samirah A.

AU - Rangel, Erika B.

AU - Premer, Courtney

AU - Dulce, Raul A.

AU - Cao, Yenong

AU - Florea, Victoria

AU - Balkan, Wayne

AU - Rodrigues, Claudia O.

AU - Schally, Andrew V.

AU - Hare, Joshua M.

PY - 2013/2/19

Y1 - 2013/2/19

N2 - Although nitric oxide (NO) signaling promotes differentiation and maturation of endothelial progenitor cells, its role in the differentiation of mesenchymal stem cells (MSCs) into endothelial cells remains controversial. We tested the role of NO signaling in MSCs derived from WT mice and mice homozygous for a deletion of S-nitrosoglutathione reductase (GSNOR-/-), a denitrosylase that regulates S-nitrosylation. GSNOR-/- MSCs exhibited markedly diminished capacity for vasculogenesis in an in vitro Matrigel tube-forming assay and in vivo relative to WT MSCs. This decrease was associated with down-regulation of the PDGF receptorα (PDGFRα) in GSNOR -/- MSCs, a receptor essential for VEGF-A action in MSCs. Pharmacologic inhibition of NO synthase with L-NG-nitroarginine methyl ester (L-NAME) and stimulation of growth hormone-releasing hormone receptor (GHRHR) with GHRH agonists augmented VEGF-A production and normalized tube formation in GSNOR-/- MSCs, whereas NO donors or PDGFR antagonist reduced tube formation ∼50% by murine and human MSCs. The antagonist also blocked the rescue of tube formation in GSNOR-/- MSCs by L-NAME or the GHRH agonists JI-38, MR-409, and MR-356. Therefore, GSNOR -/- MSCs have a deficient capacity for endothelial differentiation due to downregulation of PDGFRα related to NO/GSNOR imbalance. These findings unravel important aspects of modulation of MSCs by VEGF-A activation of the PDGFR and illustrate a paradoxical inhibitory role of S-nitrosylation signaling in MSC vasculogenesis. Accordingly, disease states characterized by NO deficiency may trigger MSC-mediated vasculogenesis. These findings have important implications for therapeutic application of GHRH agonists to ischemic disorders.

AB - Although nitric oxide (NO) signaling promotes differentiation and maturation of endothelial progenitor cells, its role in the differentiation of mesenchymal stem cells (MSCs) into endothelial cells remains controversial. We tested the role of NO signaling in MSCs derived from WT mice and mice homozygous for a deletion of S-nitrosoglutathione reductase (GSNOR-/-), a denitrosylase that regulates S-nitrosylation. GSNOR-/- MSCs exhibited markedly diminished capacity for vasculogenesis in an in vitro Matrigel tube-forming assay and in vivo relative to WT MSCs. This decrease was associated with down-regulation of the PDGF receptorα (PDGFRα) in GSNOR -/- MSCs, a receptor essential for VEGF-A action in MSCs. Pharmacologic inhibition of NO synthase with L-NG-nitroarginine methyl ester (L-NAME) and stimulation of growth hormone-releasing hormone receptor (GHRHR) with GHRH agonists augmented VEGF-A production and normalized tube formation in GSNOR-/- MSCs, whereas NO donors or PDGFR antagonist reduced tube formation ∼50% by murine and human MSCs. The antagonist also blocked the rescue of tube formation in GSNOR-/- MSCs by L-NAME or the GHRH agonists JI-38, MR-409, and MR-356. Therefore, GSNOR -/- MSCs have a deficient capacity for endothelial differentiation due to downregulation of PDGFRα related to NO/GSNOR imbalance. These findings unravel important aspects of modulation of MSCs by VEGF-A activation of the PDGFR and illustrate a paradoxical inhibitory role of S-nitrosylation signaling in MSC vasculogenesis. Accordingly, disease states characterized by NO deficiency may trigger MSC-mediated vasculogenesis. These findings have important implications for therapeutic application of GHRH agonists to ischemic disorders.

KW - Angiogenesis

KW - Nitroso-redox imbalance

UR - http://www.scopus.com/inward/record.url?scp=84874233217&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84874233217&partnerID=8YFLogxK

U2 - 10.1073/pnas.1220185110

DO - 10.1073/pnas.1220185110

M3 - Article

VL - 110

SP - 2834

EP - 2839

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 8

ER -