A successful pregnancy outcome relies on extensive maternal cardiovascular adaptation, including enhanced uteroplacental vasodilator mechanisms. The objective of the present study was to determine the contribution of the endothelium-derived hyperpolarizing factor (EDHF) signaling in pregnancy-enhanced uterine vasodilation, to define the role of Ca(2+)-activated K(+) channels in mediating EDHF effects, and to explore the impact of endothelial Ca(2+) signaling in pregnancy-specific upregulation of EDHF. Fura 2-based measurements of smooth muscle cell (SMC) and endothelial cell cytosolic Ca(2+) concentration ([Ca(2+)](i)) were performed simultaneously with measurements of the diameter of uterine radial arteries from nonpregnant (NP) and late pregnant (LP) rats. Changes in SMC membrane potential of pressurized arteries from LP rats were assessed using glass microelectrodes. After blockade of nitric oxide and prostacyclin production, a cumulative application of ACh induced rapid and effective dilatation of uterine vessels from both NP and LP rats. This vasodilation was associated with SMC hyperpolarization and SMC [Ca(2+)](i) reduction and was abolished by a high-K(+) solution, demonstrating that N(G)-nitro-L-arginine (L-NNA)- and indomethacin-resistant responses are attributable to EDHF. Pregnancy significantly potentiates EDHF-mediated vasodilation in part due to enhanced endothelial Ca(2+) signaling. L-NNA- and indomethacin-resistant responses were insensitive to iberiotoxin but abolished by a combined treatment with apamin and charybdotoxin, supporting the key role of small- and intermediate-conductance K(+) channels in mediating EDHF signaling in the maternal uterine resistance vasculature.

Normal pregnancy is associated with an increase in uteroplacental blood flow in part due to growth and remodeling of the maternal uterine vasculature. In this study, we characterized the effect of diabetic pregnancy on vascular growth of the maternal uterine vasculature and on the passive mechanical properties of the uterine resistance arteries. Diabetes was induced in pregnant rats by injection of streptozotocin and confirmed by development of hyperglycemia. Fetuses of diabetic rats were significantly smaller and placentas larger compared to controls. Pregnancy-induced axial elongation of the mesometrial uterine vasculature was not altered by diabetes. Vascular wall thickness was unchanged between groups. Wall distensibility was increased and the rate constant of an exponential function fitted to stress-strain curve was significantly reduced demonstrating decreased wall stiffness in diabetic uterine radial arteries compared to controls. We conclude that experimental diabetes in rat pregnancy does not compromise the growth of maternal uterine vasculature but alters passive mechanical properties of the uterine radial arteries.

Diabetes in pregnancy is associated with such adverse outcomes as hypertension, preeclampsia and stillbirth. Increased uteroplacental vascular resistance due to endothelial dysfunction may be an underlying mechanism. This study aimed to (1) Characterize the effect of diabetes on EDHF‐mediated uteroplacental vasodilation; (2) Explore the role of endothelial intermediate‐conductance (IKCa) K+ channels in impaired of EDHF responses. Diabetes was induced by injection of streptozotocin (STZ) on day 2 pregnant rats. Uteroplacental arteries from day 20 of pregnancy were cannulated, pressurized and loaded with fura 2. The vasodilator and smooth muscle cell (SMC) [Ca2+]i responses to ACh, EBIO or NS309 were studied in pre‐constricted arteries in the presence of L‐NNA and indomethacin. STZ injection produced sustained hyperglycemia in treated rats. ACh‐induced vasodilation and reduction in SMC [Ca2+]i were attenuated by diabetes. EDHF responses were not affected by iberiotoxin or apamin but abolished by charybdotoxin or TRAM‐34. EBIO‐ or NS309‐induced vasodilation was abolished by TRAM‐34 and was significantly impaired in hyperglycemic rats. Diabetes in pregnancy results in a marked impairment of EDHF‐mediated vasodilation most likely due to dysfunction of endothelial IKCa channels, which may serve as a target of future pharmacotherapy to improve uteroplacental blood flow.Supported by NIH HL088245