HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 74/2/375    most recent biolreprod.105.043190v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zheng, J. Articles by Chen, D.-b. Search for Related Content PubMed PubMed Citation Articles by Zheng, J. Articles by Chen, D.-b. Agricola Articles by Zheng, J. Articles by Chen, D.-b.

Exogenous Nitric Oxide Stimulates Cell Proliferation via Activation of a Mitogen-Activated Protein Kinase Pathway in Ovine Fetoplacental Artery Endothelial Cells¹

Department of Obstetrics and Gynecology, Perinatal Research Laboratories,³ University of Wisconsin, Madison, Wisconsin 53715 Department of Reproductive Medicine, Division of Maternal-Fetal Medicine,⁴ University of California, San Diego, California 92093

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 N^G-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.

cell proliferation, MAPK3/1, nitric oxide, placenta, placental endothelial cells, pregnancy, signal transduction, SNP

¹ Supported in part by National Institutes of Health grants HL64703 and HD38843S2 (J.Z.) and HL74947 and HL70562 (D.B.C.).

² Correspondence: Jing Zheng, Department of Obstetrics and Gynecology, Perinatal Research Laboratories, University of Wisconsin, Atrium Basement Meriter Hospital, 202 S. Park St., Madison, WI 53715. FAX: 608 257 1304; jzheng{at}wisc.edu

This article has been cited by other articles:

				J. Zheng, Y. Wen, Y. Song, K. Wang, D.-B. Chen, and R. R Magness Activation of Multiple Signaling Pathways Is Critical for Fibroblast Growth Factor 2- and Vascular Endothelial Growth Factor-Stimulated Ovine Fetoplacental Endothelial Cell Proliferation Biol Reprod, January 1, 2008; 78(1): 143 - 150. [Abstract] [Full Text] [PDF]

				G. Wu, F. W. Bazer, J. M. Wallace, and T. E. Spencer BOARD-INVITED REVIEW: Intrauterine growth retardation: Implications for the animal sciences J Anim Sci, September 1, 2006; 84(9): 2316 - 2337. [Abstract] [Full Text] [PDF]