Local effects of pregnancy on connexin proteins that mediate Ca2+-associated uterine endothelial NO synthesis.

UNLABELLED Uterine artery adaptations during gestation facilitate increases in uterine blood flow and fetal growth. HYPOTHESIS local expression and distribution of uterine artery connexins play roles in mediating in vivo gestational eNOS activation and NO production. We established an ovine model restricting pregnancy to a single uterine horn and measured uterine blood flow, uterine artery shear stress, connexins 37/43, and P(635)eNOS protein levels in uterine artery and systemic artery (omental and renal) endothelium and connexins in vascular smooth muscle. Uterine blood flow and shear stress were locally (unilaterally) and substantially elevated by gestation. During pregnancy, uterine artery endothelial gap junction proteins connexins 37/43 were locally regulated in the gravid horn and elevated 10.3- and 25.6-fold; uterine artery endothelial P(635)eNOS and total eNOS were elevated 3.3- and 2.9-fold; whereas uterine artery vascular smooth muscle connexins 37/43 were locally elevated 12.5- and 5.9-fold, respectively. Less pronounced changes were observed in systemic vasculature except for significant pregnancy-associated increases in omental artery vascular smooth muscle connexin 43 and omental artery endothelial P(635)eNOS and total eNOS. Gap junction blockade using connexin 43, but not connexin 37-specific Gap peptides, abrogated uterine artery endothelial ATP-induced Ca(2+)-mediated NO production. Thus, uterine artery endothelial connexin 43, but not connexin 37, regulates Ca(2+)-mediated NO production required for the vasodilation to accommodate increases in uterine blood flow and shear stress during healthy pregnancies.