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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.

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