Pregnancy modifies the large conductance Ca²⁺-activated K⁺ channel and cGMP-dependent signaling pathway in uterine vascular smooth muscle

Abstract

Regulation of uteroplacental blood flow (UPBF) during pregnancy remains unclear. Large conductance, Ca(2+)-activated K(+) channels (BK(Ca)), consisting of alpha- and regulatory beta-subunits, are expressed in uterine vascular smooth muscle (UVSM) and contribute to the maintenance of UPBF in the last third of ovine pregnancy, but their expression pattern and activation pathways are unclear. We examined BK(Ca) subunit expression, the cGMP-dependent signaling pathway, and the functional role of BK(Ca) in uterine arteries (UA) from nonpregnant (n = 7), pregnant (n = 38; 56-145 days gestation; term, approximately 150 days), and postpartum (n = 15; 2-56 days) sheep. The alpha-subunit protein switched from 83-87 and 105 kDa forms in nonpregnant UVSM to 100 kDa throughout pregnancy, reversal occurring >30 days postpartum. The 39-kDa beta(1)-subunit was the primary regulatory subunit. Levels of 100-kDa alpha-subunit rose approximately 70% during placentation (P < 0.05) and were unchanged in the last two-thirds of pregnancy; in contrast, beta(1)-protein rose throughout pregnancy (R(2) = 0.996; P < 0.001; n = 13), increasing 50% during placentation and approximately twofold in the remainder of gestation. Although UVSM soluble guanylyl cyclase was unchanged, cGMP and protein kinase G(1alpha) increased (P < 0.02), paralleling the rise and fall in beta(1)-protein during pregnancy and the puerperium. BK(Ca) inhibition not only decreased UA nitric oxide (NO)-induced relaxation but also enhanced alpha-agonist-induced vasoconstriction. UVSM BK(Ca) modify relaxation-contraction responses in the last two-thirds of ovine pregnancy, and this is associated with alterations in alpha-subunit composition, alpha:beta(1)-subunit stoichiometry, and upregulation of the cGMP-dependent pathway, suggesting that BK(Ca) activation via NO-cGMP and beta(1) augmentation may contribute to the regulation of UPBF.

Prolonged uterine artery nitric oxide synthase inhibition modestly alters basal uteroplacental vasodilation in the last third of ovine pregnancy

“…While it is clear that NO contributes to basal UPBF regulation, it is not the primary pathway, confirming earlier reports (27,35). We and others (13,34,38) have shown that large-conductance Ca 2ϩ -activated K ϩ (BK Ca ) channels are major contributors to the maintenance of basal ovine UPBF; e.g., unilateral BK Ca channel inhibition decreases basal UPBF Ն80% without affecting the noninfused uterine horn or cGMP synthesis. BK Ca channel activation occurs via the NOS-NO-cGMP-PKG pathway and/or direct activation by estrogens via the ␤ 1 -regulatory subunit, which is upregulated in the UA during the last third of ovine pregnancy (8,9,41,50).…”

Pregnancy increases myometrial artery myogenic tone via NOS- or COX-independent mechanisms

“…There also may be differences in the expression and/or function of vascular smooth muscle K ϩ channels that contribute to myogenic responses and have been identified in the uteroplacental circulation, e.g., K v and BK Ca (32,39,43,50). These channels have been identified in women (43), sheep (37), and rat (41,50) uterine arteries and shown to modify maternal uterine blood flow (18,42), but their expression and function in human MA is not known. Whereas BK Ca channels appear to modulate uterine vasodilation and vasoconstriction in women and sheep (39,41,43), downregulation and/or inactivation of K v channels is associated with increased myogenic responses in small uterine arteries from pregnant rats (50).…”

The renal circulation in normal pregnancy and preeclampsia: is there a place for relaxin?

“…38). In contrast, endothelium-derived hyperpolarizing factor (83,86,114,123,124,126,164,175), K ATP ϩ channel activation (100) and endothelium-derived relaxing factor (EDRF) or nitric oxide (NO) (175) autocoid was implicated in the vasodilatory phenomena of pregnancy (28,43). Later, evidence for increased NO biosynthesis was reported in gravid rats (37).…”