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1 OB/Gyn, University Wisconsin, Madison, Wi, USA
2 OB/Gyn, University Wisconsin, Madison, Wi, USA; Animal Science, University Wisconsin, Madison, Wi, USA
* To whom correspondence should be addressed. E-mail: imbird{at}wisc.edu.
Pregnancy, and the follicular phase of the ovarian cycle show elevation of uterine blood flow and associated increases in uterine artery endothelium (UAE) eNOS expression. Nonetheless, a role for increased NO production during pregnancy and the follicular phase has only been inferred by indirect measures. The recent development of a uterine artery endothelial cell (UAEC) model further suggests pregnancy is associated with reprogramming of cell signaling such that eNOS may become more Ca2+-sensitive and be subject to regulation by Ca2+-independent kinases. This study describes for the first time the direct and simultaneous monitoring of NO production and intracellular free Ca2+ concentration ([Ca2+]i) in freshly isolated UAE from pregnant (P), follicular (F), and luteal (L) sheep. The pharmacological agonists ionomycin (calcium ionophore) and thapsigargin (TG - endoplasmic reticulum Ca2+ pump inhibitor), were used to maximally elevate [Ca2+]i, and fully activate eNOS as a measure of eNOS expression. NO production stimulated by ionomycin (5 µM) vs TG (10 µmM) were 1.95 /2.05 fold respectively in P-UAE and 1.34/1.37 fold in F-UAE compared to L-UAE. In contrast, the physiologic agonist, ATP (100 µM), stimulated a 3.43 fold increase in NO in P-UAE and 1.90 fold in F-UAE compared to L-UAE, suggesting pregnancy and follicular phase enhance eNOS activation beyond changes in expression in vivo. 2-APB (an IP3-R blocker) totally prevented the ATP-induced [Ca2+]i response, but only partially inhibited NO production. Thus pregnancy-enhanced eNOS activation in UAE is mediated through [Ca2+]i-insensitive pathways as well as through a greater eNOS sensitivity to [Ca2+]i.
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