Direct chronic effect of steroid hormones in attenuating uterine arterial myogenic tone: role of protein kinase c/extracellular signal-regulated kinase 1/2.
Pregnancy is associated with a significant decrease in uterine vascular tone and an increase in uterine blood flow. The present study tested the hypothesis that estrogen and progesterone differentially regulate the extracellular signal-regulated kinase (ERK)1/2 and protein kinase C (PKC) signaling pathways in vascular smooth muscle, resulting in a decrease in uterine vascular myogenic tone in pregnancy. Uterine arteries were isolated from nonpregnant and near-term pregnant sheep. Chronic treatment (48 hours) of nonpregnant uterine arteries with 17beta-estradiol and progesterone caused a significant decrease in PKC-mediated contractions and pressure-induced myogenic tone. In accordance, treatment of near-term pregnant uterine arteries for 48 hours with ICI 182780 and RU 486 significantly increased PKC-induced contractions and myogenic tone. In contrast, acute treatment for 30 minutes had no effect on uterine artery contractility. An ERK1/2 inhibitor, PD098059, restored the chronic effect of steroids on PKC-mediated contractions in nonpregnant sheep. ERK1/2 protein and mRNA levels were greater in near-term pregnant as compared with nonpregnant uterine arteries. 17beta-Estradiol and progesterone increased ERK1/2 protein in nonpregnant sheep. In agreement, ICI 182780 and RU 486 caused significant decreases in ERK1/2 protein in near-term pregnant sheep. Western blot showed 6 PKC isozymes, alpha, beta(I), beta(II), delta, epsilon, and zeta, in the uterine arteries. 17beta-Estradiol and progesterone decreased the particulate:cytosolic ratios of PKCalpha, epsilon, and zeta, respectively, in nonpregnant sheep. ICI 182780 and RU 486 increased the ratios in near-term pregnant sheep. The results indicate a direct chronic effect of the steroid hormones in the upregulation of ERK1/2 expression and downregulation of the PKC signaling pathway, resulting in attenuated myogenic tone of the uterine artery in pregnancy.
Xiao
Daliao
D
Center for Perinatal Biology, Department of Physiology and Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA 92350,USA.
Huang
Xiaohui
X
Yang
Shumei
S
Zhang
Lubo
L
D000704:Analysis of Variance; D000818:Animals; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D048052:Mitogen-Activated Protein Kinase 3 / Q000187:drug effects / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009215:Myometrium / Q000187:drug effects / Q000502:physiology; D011247:Pregnancy; D011270:Pregnancy, Animal; D011336:Probability; D011374:Progesterone / Q000494:pharmacology*; D011493:Protein Kinase C / Q000187:drug effects / Q000378:metabolism*; D011897:Random Allocation; D012016:Reference Values; D012680:Sensitivity and Specificity; D012756:Sheep; D015398:Signal Transduction / Q000502:physiology; D046509:Tissue Culture Techniques; D015854:Up-Regulation; D014590:Uterine Contraction / Q000187:drug effects* / Q000502:physiology; D014599:Uterus / Q000098:blood supply*; D014655:Vascular Resistance / Q000502:physiology
D004791:Enzyme Inhibitors; D011374:Progesterone; D004958:Estradiol; D011493:Protein Kinase C; D048052:Mitogen-Activated Protein Kinase 3