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Fetal Physiological Programming

Simultaneous imaging of [Ca²⁺]_i and intracellular NO production in freshly isolated uterine artery endothelial cells: effects of ovarian cycle and pregnancy

Perinatal Research Laboratories, Departments of ¹Obstetrics/Gynecology, and ²Animal Science, University of Wisconsin-Madison, Madison, Wisconsin

Submitted 6 May 2004 ; accepted in final form 4 August 2004

Pregnancy and the follicular phase of the ovarian cycle show elevation of uterine blood flow and associated increases in uterine artery endothelium (UAE) endothelial nitric oxide (NO) synthase (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 model further suggests that 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, follicular, and luteal 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) and TG (10 µM) were 1.95- and 2.05-fold, respectively, in pregnant-UAE and 1.34- and 1.37-fold in follicular-UAE compared with luteal-UAE. In contrast, the physiological agonist ATP (100 µM) stimulated a 3.43-fold increase in NO in pregnant-UAE and a 1.90-fold increase in follicular-UAE compared with luteal-UAE, suggesting that pregnancy and follicular phase enhance eNOS activation beyond changes in expression in vivo. 2-aminoethoxydiphenyl borate (APB; an inositol 1,4,5-trisphosphate receptor 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.

endothelium; nitric oxide; follicular; kinase; programming; intracellular free calcium concentration

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