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Submitted on April 6, 2005
Accepted on January 20, 2006
Departments of Obstetrics & Gynecology, Perinatal Research Laboratories, University of Wisconsin, Madison WI 53715
* To whom correspondence should be addressed. E-mail: Imbird{at}wisc.edu.
During pregnancy, vascular remodeling and vasoactive agents such as nitric oxide (NO) increase blood flow to the uteroplacental unit. Using our Uterine Artery Endothelial Cell culture model, based on cells from pregnant (P-UAEC) and nonpregnant (NP-UAEC) ewes, we investigate the relative physiologic roles of Ca2+ vs. kinase in the regulation of eNOS activity. When Ca2+ mobilization is fully inhibited using inhibitors of PLC (U73122) and the IP3 receptor (2-APB), significant residual eNOS activity in both P and NP-UAEC remains. No change in ATP stimulated ERK2, Akt or eNOS phosphorylation with U73122 (0.01-1 µM) or 2-APB (1-50 µM) is observed. The MEK 1/2 inhibitor U0126 (10 µM) did not alter ATP stimulated eNOS activity in P-UAEC, but potentiated the ATP response in NP-UAEC. Using two PI3K inhibitors, we observed no effect with LY294002 (10 µM) on eNOS activity in P and NP-UAEC, but wortmannin (10 µM) inhibited both P and NP-UAEC eNOS activation. Expression of constitutively active Akt (ca-Akt) in UAEC resulted in slight elevation of basal eNOS activity, but relative ATP stimulated eNOS activation was not altered by ca-Akt. Wortmannin continued to inhibit eNOS activation by ATP in the presence of ca-Akt; LY294002 still had no inhibitory effect. Our data indicate both [Ca2+]i and multiple kinases are involved in the regulation of eNOS activity in our model. We report pregnancy adaptation of eNOS activation includes the reduced sensitivity to ERK mediated attenuation of eNOS activity and enhanced stimulation of eNOS activity though a wortmannin sensitive, LY294002 insensitive, Akt independent mechanism.
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