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

Charles R. Rosenfeld, Xiao Tie Liu, Kevin DeSpain

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33 Citations (Scopus)

Abstract

Regulation of uteroplacental blood flow (UPBF) during pregnancy remains unclear. Large conductance, Ca2+-activated K+ channels (BKCa), consisting of α- 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 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 α-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 α-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 G increased (P < 0.02), paralleling the rise and fall in β1-protein during pregnancy and the puerperium. BKCa inhibition not only decreased UA nitric oxide (NO)-induced relaxation but also enhanced α-agonist-induced vasoconstriction. UVSM BKCa modify relaxation-contraction responses in the last two-thirds of ovine pregnancy, and this is associated with alterations in α-subunit composition, α:β1-subunit stoichiometry, and upregulation of the cGMP-dependent pathway, suggesting that BKCa activation via NO-cGMP and β1 augmentation may contribute to the regulation of UPBF.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume296
Issue number6
DOIs
StatePublished - Jun 2009

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Calcium-Activated Potassium Channels
Vascular Smooth Muscle
Pregnancy
Postpartum Period
Placentation
Uterine Artery
Sheep
Nitric Oxide
Pregnancy Proteins
Cyclic GMP-Dependent Protein Kinases
Protein Subunits
Vasoconstriction
Up-Regulation
Maintenance

Keywords

  • Cyclic guanosine 3′,5′-monophosphate
  • Protein kinase G isoforms
  • Regulatory subunits
  • Uteroplacental blood flow

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

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title = "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, Ca2+-activated K+ channels (BKCa), consisting of α- 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 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 α-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 α-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 G 1α increased (P < 0.02), paralleling the rise and fall in β1-protein during pregnancy and the puerperium. BKCa inhibition not only decreased UA nitric oxide (NO)-induced relaxation but also enhanced α-agonist-induced vasoconstriction. UVSM BKCa modify relaxation-contraction responses in the last two-thirds of ovine pregnancy, and this is associated with alterations in α-subunit composition, α:β1-subunit stoichiometry, and upregulation of the cGMP-dependent pathway, suggesting that BKCa activation via NO-cGMP and β1 augmentation may contribute to the regulation of UPBF.",
keywords = "Cyclic guanosine 3′,5′-monophosphate, Protein kinase G isoforms, Regulatory subunits, Uteroplacental blood flow",
author = "Rosenfeld, {Charles R.} and Liu, {Xiao Tie} and Kevin DeSpain",
year = "2009",
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language = "English (US)",
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journal = "American Journal of Physiology - Heart and Circulatory Physiology",
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T1 - Pregnancy modifies the large conductance Ca2+-activated K + channel and cGMP-dependent signaling pathway in uterine vascular smooth muscle

AU - Rosenfeld, Charles R.

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AU - DeSpain, Kevin

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N2 - Regulation of uteroplacental blood flow (UPBF) during pregnancy remains unclear. Large conductance, Ca2+-activated K+ channels (BKCa), consisting of α- 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 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 α-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 α-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 G 1α increased (P < 0.02), paralleling the rise and fall in β1-protein during pregnancy and the puerperium. BKCa inhibition not only decreased UA nitric oxide (NO)-induced relaxation but also enhanced α-agonist-induced vasoconstriction. UVSM BKCa modify relaxation-contraction responses in the last two-thirds of ovine pregnancy, and this is associated with alterations in α-subunit composition, α:β1-subunit stoichiometry, and upregulation of the cGMP-dependent pathway, suggesting that BKCa activation via NO-cGMP and β1 augmentation may contribute to the regulation of UPBF.

AB - Regulation of uteroplacental blood flow (UPBF) during pregnancy remains unclear. Large conductance, Ca2+-activated K+ channels (BKCa), consisting of α- 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 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 α-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 α-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 G 1α increased (P < 0.02), paralleling the rise and fall in β1-protein during pregnancy and the puerperium. BKCa inhibition not only decreased UA nitric oxide (NO)-induced relaxation but also enhanced α-agonist-induced vasoconstriction. UVSM BKCa modify relaxation-contraction responses in the last two-thirds of ovine pregnancy, and this is associated with alterations in α-subunit composition, α:β1-subunit stoichiometry, and upregulation of the cGMP-dependent pathway, suggesting that BKCa activation via NO-cGMP and β1 augmentation may contribute to the regulation of UPBF.

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