This Article Full Text Full Text (PDF) 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 Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Di, T. Articles by Bird, I. M. Search for Related Content PubMed PubMed Citation Articles by Di, T. Articles by Bird, I. M.

Pregnancy-Specific Enhancement of Agonist-Stimulated ERK-1/2 Signaling in Uterine Artery Endothelial Cells Increases Ca²⁺ Sensitivity of Endothelial Nitric Oxide Synthase as well as Cytosolic Phospholipase A₂¹

Perinatal Research Laboratories, Departments of Obstetrics/Gynecology (T.D., J.A.S., R.R.M.) and Meat/Animal Sciences (R.R.M.), University of Wisconsin-Madison, Madison, Wisconsin 53715; and Center for Perinatal Biology (L.Z.), Loma Linda University School of Medicine, Loma Linda, California 92350

Address all correspondence and requests for reprints to: Ian M. Bird, Ph.D., University Wisconsin-Madison, Department of Obstetrics and Gynecology, Perinatal Research Laboratories, 7E Meriter Hospital/Park, 202 South Park Street, Madison, Wisconsin 53715. E-mail: imbird{at}facstaff.wisc.edu

Uterine artery endothelial cells (UAEC) from pregnant ewes (P-UAEC) demonstrate generally enhanced ability to couple growth factor and G protein-coupled receptors to the ERK-1/2 signaling pathway and stimulate NO production independently of elevated [Ca²⁺]. Herein we investigate the signaling and vasodilator responses to ATP, an agonist that also elevates [Ca²⁺]_i in both NP and P-UAEC, to determine the relative importance of Ca²⁺ vs. ERK-1/2 in the activation of eNOS. We observed in both NP-UAEC and P-UAEC that ATP acts through G protein-coupled P_2Y receptors to activate phospholipase C and dose-dependently elevate [Ca²⁺]_i independently of extracellular Ca²⁺. The small reduction in the [Ca²⁺]_i response in NP vs. P-UAEC did not, however, account for the difference in NO production by P-UAEC>>NP-UAEC. ATP had no stimulatory effect on Akt phosphorylation but rapidly stimulated ERK-1/2 phosphorylation in P-UAEC>>NP-UAEC in a manner that correlated with NO production. In both NP- and P-UAEC, both ERK-1/2 and Ca²⁺ were absolutely required for eNOS as well as cPLA₂ activation and the Ca²⁺ sensitivity of eNOS was enhanced through the cytosolic [Ca²⁺]_i range in P-UAEC>>NP-UAEC. Thus ERK-1/2 may regulate the Ca²⁺ sensitivity of eNOS to an even greater extent than is known to occur for cPLA₂.

This article has been cited by other articles:

				K. Chang and Lubo Zhang Review Article: Steroid Hormones and Uterine Vascular Adaptation to Pregnancy Reproductive Sciences, April 1, 2008; 15(4): 336 - 348. [Abstract] [PDF]

				S. M Gifford, F.-X. Yi, and I. M Bird Pregnancy-enhanced Ca2+ responses to ATP in uterine artery endothelial cells is due to greater capacitative Ca2+ entry rather than altered receptor coupling. J. Endocrinol., August 1, 2006; 190(2): 373 - 384. [Abstract] [Full Text] [PDF]

				D. Xiao, J. N. Buchholz, and L. Zhang Pregnancy attenuates uterine artery pressure-dependent vascular tone: role of PKC/ERK pathway Am J Physiol Heart Circ Physiol, June 1, 2006; 290(6): H2337 - H2343. [Abstract] [Full Text] [PDF]

				J. A. Sullivan, M. A. Grummer, F.-X. Yi, and I. M. Bird Pregnancy-Enhanced Endothelial Nitric Oxide Synthase (eNOS) Activation in Uterine Artery Endothelial Cells Shows Altered Sensitivity to Ca2+, U0126, and Wortmannin But Not LY294002--Evidence that Pregnancy Adaptation of eNOS Activation Occurs at Multiple Levels of Cell Signaling Endocrinology, May 1, 2006; 147(5): 2442 - 2457. [Abstract] [Full Text] [PDF]

				N. I. Gokina and T. Goecks Upregulation of endothelial cell Ca2+ signaling contributes to pregnancy-enhanced vasodilation of rat uteroplacental arteries Am J Physiol Heart Circ Physiol, May 1, 2006; 290(5): H2124 - H2135. [Abstract] [Full Text] [PDF]

				J. M. Cale and I. M. Bird Dissociation of endothelial nitric oxide synthase phosphorylation and activity in uterine artery endothelial cells Am J Physiol Heart Circ Physiol, April 1, 2006; 290(4): H1433 - H1445. [Abstract] [Full Text] [PDF]

				F.-X. Yi and I. M. Bird Pregnancy-Specific Modulatory Role of Mitochondria on Adenosine 5'-Triphosphate-Induced Cytosolic [Ca2+] Signaling in Uterine Artery Endothelial Cells Endocrinology, November 1, 2005; 146(11): 4844 - 4850. [Abstract] [Full Text] [PDF]

				J. M. Cale, S. C. Tsoi, M. Toppe, M. A. Grummer, M. Ochiai, R. R. Magness, and I. M. Bird Molecular Cloning of Ovine Endothelial Nitric Oxide Synthase and Expression in COS-7 Cells Reproductive Sciences, April 1, 2005; 12(3): 156 - 168. [Abstract] [PDF]

				F.-X. Yi, R. R. Magness, and I. M. Bird Simultaneous imaging of [Ca2+]i and intracellular NO production in freshly isolated uterine artery endothelial cells: effects of ovarian cycle and pregnancy Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2005; 288(1): R140 - R148. [Abstract] [Full Text] [PDF]

				D. Xiao and L. Zhang Adaptation of uterine artery thick- and thin-filament regulatory pathways to pregnancy Am J Physiol Heart Circ Physiol, January 1, 2005; 288(1): H142 - H148. [Abstract] [Full Text] [PDF]

				S. M. Gifford, J. M. Cale, S. Tsoi, R. R. Magness, and I. M. Bird Pregnancy-Specific Changes in Uterine Artery Endothelial Cell Signaling in Vivo Are Both Programmed and Retained in Primary Culture Endocrinology, August 1, 2003; 144(8): 3639 - 3650. [Abstract] [Full Text] [PDF]

				I. M. Bird, L. Zhang, and R. R. Magness Possible mechanisms underlying pregnancy-induced changes in uterine artery endothelial function Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2003; 284(2): R245 - R258. [Abstract] [Full Text] [PDF]

				T. Kimura, K. Ayajiki, Y. Noda, and T. Okamura Comparison of the Responses to Thrombin in Monkey Renal and Uterine Arteries Reproductive Sciences, May 1, 2002; 9(3): 146 - 151. [Abstract] [PDF]

				D. Xiao and L. Zhang ERK MAP kinases regulate smooth muscle contraction in ovine uterine artery: effect of pregnancy Am J Physiol Heart Circ Physiol, January 1, 2002; 282(1): H292 - H300. [Abstract] [Full Text] [PDF]

				J. M. Joyce, T. M. Phernetton, C. E. Shaw, M. L. Modrick, and R. R. Magness Endothelial vasodilator production by uterine and systemic arteries. IX. eNOS gradients in cycling and pregnant ewes Am J Physiol Heart Circ Physiol, January 1, 2002; 282(1): H342 - H348. [Abstract] [Full Text] [PDF]

				J. K. Peterson, F. Moran, A. J. Conley, and I. M. Bird Zonal Expression of Endothelial Nitric Oxide Synthase in Sheep and Rhesus Adrenal Cortex Endocrinology, December 1, 2001; 142(12): 5351 - 5363. [Abstract] [Full Text] [PDF]