A successful pregnancy and delivery require two distinct states of uterine activity: a quiescent state characterized by weak, asynchronous, regional contractions throughout pregnancy; and an activated state in which contractions increase in force, frequency, and synchrony to expel the fetus at term. These states are controlled by electrical activity of the uterine (myometrial) smooth muscle cells (MSMCs). Two key ions regulate MSMC electrical activity: calcium (Ca2+), which enters the cell, depolarizes the membrane, and activates the contractile machinery; and potassium (K+), which effluxes from the cell, repolarizes (inside of the membrane more negative than outside) the membrane, and returns the cell to the resting state. The traditional model is that Ca2+ enters through voltage-gated Ca2+ (Cav) channels and activates the large-conductance Ca2+-activated K+ channel KCa1.1. Here, we propose that whereas this model explains the basal, quiescent state, it is insufficient to explain the activated, inflammatory state characteristic of term labor. Instead, we propose a new model in which low KCa1.1 activity and Cav-mediated Ca2+ influx maintain MSMC membrane polarization in basal states, but high KCa1.1 activity and Ca2+ influx through store-operated Ca2+ (SOC) channels are required for membrane repolarization in inflammatory states. This new model is founded on several pieces of published and preliminary data. First, KCa1.1 is substantially more active in MSMCs isolated from laboring women than in those from non-laboring women. Second, when the inflammatory protein alpha-2- macroglobulin (?2M) binds to its receptor, low density lipoprotein receptor-related protein 1 (LRP1), KCa1.1 activity enhances Ca2+ oscillations in MSMCs. Third, these Ca2+ oscillations are not inhibited by the Cav blocker nifedipine, but by SOC inhibitors. Finally, in MSMCs, KCa1.1 interacts with ?2?1, the subunit that traffics Cav to the plasma membrane. To test our model, we will pursue three specific aims: 1) Determine the extent to which KCa1.1 is required for MSMC excitability in basal and inflammatory states; 2) Define the mechanism by which inflammatory stimuli enhance KCa1.1 and Ca2+ channel activity; and 3) Determine the mechanism by which KCa1.1 inhibits Cav-mediated Ca2+ influx. Insights gained from this work may lead to new therapeutic strategies to modulate uterine excitability and prevent aberrant uterine activity.

Public Health Relevance

This proposal tests a novel model about the function of a key ion channel controlling contraction of uterine muscle cells. Information learned from the proposed studies will, in the long term, lead to development of new methods to treat and prevent pregnancy complications such as preterm and post-term labor.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
2R01HD037831-17A1
Application #
9887548
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Ilekis, John V
Project Start
1999-06-01
Project End
2024-07-31
Budget Start
2019-09-25
Budget End
2020-07-31
Support Year
17
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Washington University
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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