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

Rosenfeld CR, Liu X, DeSpain K. Pregnancy modifies the large conductance Ca -activated K channel and cGMP-dependent signaling pathway in uterine vascular smooth muscle. Am J Physiol Heart Circ Physiol 296: H1878–H1887, 2009; doi:10.1152/ajpheart.01185.2008.— Regulation of uteroplacental blood flow (UPBF) during pregnancy remains unclear. Large conductance, Ca -activated K channels (BKCa), consisting of and regulatory -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 BKCa subunit expression, the cGMP-dependent signaling pathway, and the functional role of BKCa 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 1-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, 1-protein rose throughout pregnancy (R 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 1-protein during pregnancy and the puerperium. BKCa inhibition not only decreased UA nitric oxide (NO)-induced relaxation but also enhanced -agonist-induced vasoconstriction. UVSM BKCa modify relaxationcontraction responses in the last two-thirds of ovine pregnancy, and this is associated with alterations in -subunit composition, : 1subunit stoichiometry, and upregulation of the cGMP-dependent pathway, suggesting that BKCa activation via NO-cGMP and 1 augmentation may contribute to the regulation of UPBF.