Pregnancy is associated with a significant decrease in uterine vascular tone and a striking increase in uterine blood flow, which ensures normal fetal development. Multiple mechanisms are involved in the adaptation of uterine artery contractility during pregnancy. Both protein kinase C (PKC) and activation of ai-adrenoceptors play important roles in the regulation of uterine artery contractility. In addition, PKC mediates the pregnancyassociated decrease in myogenic tone of the uterine artery, and interacts with ajadrenoceptors leading to modulation of ai-adrenoceptor-mediated contractions of vascular smooth muscle. Yet, whether or to what extent PKC regulates ai-adrenoceptormediated contractions of the uterine artery and their adaptation to pregnancy remains unclear. The central hypothesis of the proposed studies is that PKC activation differentially regulates ai-adrenoceptor-mediated Ca2+ mobilization and sensitization in pregnant and nonpregnant uterine arteries. To test this hypothesis, we proposed a series of experiments in the uterine arteries obtained from nonpregnant and near-term (~140 Days) pregnant sheep.
We found that PKC activation has opposite effects on ai-adrenoceptor-mediated contractions in pregnant and nonpregnant uterine arteries. In pregnant uterine arteries PKC activation inhibited ai-adrenoceptor-mediated contractions through suppressing Ca2+ -dependent thick-filament regulatory pathway with decreased Ca2+ mobilization and phosphorylation of 20-kDa regulatory light chain of myosin (LC20). This inhibitory effect of PKC activation was reversed by PKC isozyme-selective inhibitory peptides for PKCpi, (311 and s. In contrast, in nonpregnant uterine arteries PKC activation potentiated a 1-adrenoceptor-mediated contractions through enhancing thin- filament regulatory pathway with increased Ca" sensitivity and phosphorylation of extracellular signal- 70Q regulated kinase44/42 (ERK44/42) and Caldesmon-Ser without changing the phosphorylation level of LC20. This potentiating effect of PKC activation was reversed by PKC isozyme-selective inhibitory peptides for conventional PKCs, PKCpi, pil and c. The differential regulation of PKC isozyme expression, basal activity and reactivity, with the up-regulation of PKCp and PKC^, and the down-regulation of PKCa and PKCs, is PKCe likely to play an important role in the regulation of Ca2+ mobilization and Ca sensitivity in a 1-adrenoceptor-mediated contractions and their adaptation to pregnancy.
Ian M. Bird
Charles A. Ducsay
Raymond D. Gilbert
William J. Pearce
Doctor of Philosophy (PhD)
Year Degree Awarded
Date (Title Page)
Library of Congress/MESH Subject Headings
Protein Kinase C -- pharmacology; Uterus -- blood supply; Smooth Muscle -- physiology; Muscle Contraction; Pregnancy -- physiology.
Loma Linda University Libraries
This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights.
Zhang, Hongying, "Regulation of alpha-1-adrenoceptor-mediated contractions of the uterine artery by PKC" (2007). Loma Linda University Electronic Theses, Dissertations & Projects. 823.
Loma Linda University Electronic Theses and Dissertations
Loma Linda University. Del E. Webb Memorial Library. University Archives