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

Division of Neonatal-Perinatal Medicine, Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas

Submitted 12 November 2008 ; accepted in final form 2 March 2009

Regulation of uteroplacental blood flow (UPBF) during pregnancy remains unclear. Large conductance, Ca²⁺-activated K⁺ channels (BK_Ca), consisting of - and regulatory β-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, 150 days), and postpartum (n = 15; 2–56 days) sheep. The -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 β₁-subunit was the primary regulatory subunit. Levels of 100-kDa -subunit rose 70% during placentation (P < 0.05) and were unchanged in the last two-thirds of pregnancy; in contrast, β₁-protein rose throughout pregnancy (R² = 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 G₁ increased (P < 0.02), paralleling the rise and fall in β₁-protein during pregnancy and the puerperium. BK_Ca inhibition not only decreased UA nitric oxide (NO)-induced relaxation but also enhanced -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 -subunit composition, :β₁-subunit stoichiometry, and upregulation of the cGMP-dependent pathway, suggesting that BK_Ca activation via NO-cGMP and β₁ augmentation may contribute to the regulation of UPBF.

uteroplacental blood flow; regulatory subunits; protein kinase G isoforms; cyclic guanosine 3',5'-monophosphate