S-nitrosoglutathione reductase (GSNOR) enhances vasculogenesis by mesenchymal stem cells
S-nitrosoglutathione reductase (GSNOR) enhances vasculogenesis by mesenchymal stem cells
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DOI：
10.1073/pnas.1220185110
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发表时间：
2013-02-19
影响因子：
11.1
通讯作者：
Hare, Joshua M.
中科院分区：
文献类型：
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作者：
Gomes, Samirah A.;Rangel, Erika B.;Hare, Joshua M.
尽管一氧化氮(NO)信号促进内皮祖细胞的分化和成熟，但其在间充质干细胞(MSCs)向内皮细胞分化中的作用仍存在争议。我们测试了来自WT小鼠和S亚硝基谷胱甘肽还原酶(GSNOR(-/-))纯合子小鼠的MSCs中NO信号的作用。GSNOR(-/-)是一种调节S亚硝化的脱氮酶。与WT MSCs相比，GSNOR(-/-)MSCs在体外Matrigel管形成实验和体内实验中的血管生成能力明显降低。这一下降与GSNOR(-/-)MSCs中PDGF受体α(PDGFRα)下调有关，GSNOR(-/-)MSCs是MSCs中VEGF-A活动所必需的受体。用L-N-G-硝基精氨酸甲酯(L-NAME)抑制一氧化氮合酶，用生长激素释放激素激动剂刺激生长激素释放激素受体，可增加GSNOR(-/-)间充质干细胞血管内皮生长因子-A的生成和归一化管的形成，而NO供体或PDGFR拮抗剂使小鼠和人MSCs的管形成减少约50%。该拮抗剂还阻断了L-NAME或生长激素释放激素激动剂JI-38、MR-409和MR-356对GSNOR(-/-)MSCs的解救作用。因此，由于与NO/GSNOR失衡相关的PDGFRα表达下调，GSNOR(-/-)MSCs的内皮分化能力不足。这些发现揭示了血管内皮生长因子-A激活血管内皮生长因子受体调控间充质干细胞的重要方面，并阐明了S-硝化信号在骨髓间充质干细胞血管生成中的矛盾抑制作用。因此，以NO缺乏为特征的疾病状态可能会触发MSC介导的血管生成。这些发现对GHRH激动剂治疗缺血性疾病有重要意义。
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 receptor alpha (PDGFR alpha) in GSNOR(-/-) MSCs, a receptor essential for VEGF-A action in MSCs. Pharmacologic inhibition of NO synthase with L-N-G-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 similar to 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 PDGFR alpha 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.