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1 February 2006 Exogenous Nitric Oxide Stimulates Cell Proliferation via Activation of a Mitogen-Activated Protein Kinase Pathway in Ovine Fetoplacental Artery Endothelial Cells
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Abstract

Sodium nitroprusside (SNP), a nitric oxide (NO) donor and a nitrovasodilator drug used for patients with hypertensive crisis, has been shown to promote angiogenesis. However, direct evidence showing the involvement of NO in the SNP-induced angiogenesis is not available. Accordingly, we assessed whether NO generated from SNP-stimulated ovine fetoplacental artery endothelial (OFPAE) cell proliferation via activation of mitogen-activated protein kinase 3/1 (MAPK3/1, also termed ERK1/2). We observed that SNP dose dependently stimulated (P < 0.05) cell proliferation with a maximal effect at 1 μM and that SNP rapidly (≤15 min) phosphorylated (P < 0.05) MAPK3/1 but not v-akt murine thymoma viral oncogene homolog 1 (AKT1). Treatment of cells with SNP caused a rapid increase in NO levels in media. These increased NO levels were inhibited (P < 0.05) by 2-phenyl-4,4,5,5 tetramethylimidazoline-1-oxyl 3-oxide (PTIO), a NO scavenger. The SNP-induced cell proliferation and MAPK3/1 phosphorylation were attenuated (P < 0.05) by both PTIO and PD98059, a specific mitogen-activated protein kinase kinase 1 and 2 (MAP2K1/2, also termed MEK1/2) inhibitor. Using a semiquantitative RT-PCR analysis, we also showed that up to 12 h of treatment, SNP and NG-monomethyl-l-arginine (l-NMMA, a NOS inhibitor) did not alter mRNA expression of VEGF, FGF2, and their major receptors in OFPAE cells. The SNP's stimulatory effects on OFPAE cell proliferation and MAPK3/1 activation were confirmed in a human placental artery endothelial (HPAE) cell line. These data indicate that exogenous NO generated from SNP is able to stimulate fetoplacental artery endothelial cell proliferation at least partly via activation of the MAP2K1/2/MAPK3/1 cascade. These data also suggest that SNP could potentially be used to modulate placental angiogenesis.

Jing Zheng, YunXia Wen, Jason L. Austin, and Dong-bao Chen "Exogenous Nitric Oxide Stimulates Cell Proliferation via Activation of a Mitogen-Activated Protein Kinase Pathway in Ovine Fetoplacental Artery Endothelial Cells," Biology of Reproduction 74(2), 375-382, (1 February 2006). https://doi.org/10.1095/biolreprod.105.043190
Received: 25 April 2005; Accepted: 1 October 2005; Published: 1 February 2006
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