# Mechanisms by which the myometrial ECM modulates myometrial cell function

> **NIH NIH R00** · UNIVERSITY OF VERMONT & ST AGRIC COLLEGE · 2021 · $244,915

## Abstract

ABSTRACT
Preterm birth is a leading cause of infant mortality and can lead to long term health challenges in survivors.
Fifteen million children are born prematurely worldwide on an annual basis. Identification of risk factors and
development of preventative therapies against preterm birth require improved understanding of the molecular
processes that drive parturition at term. Over the course of pregnancy the uterus grows and remodels to
accommodate the growing fetus yet remains quiescent until term when the uterus transforms to a contractile
state for successful delivery. Fetal, mechanical, hormonal and inflammatory signals collectively regulate the
balance between myometrial quiescence and contractility though our understanding of the molecular details
remains incomplete. Increased synthesis of extracellular matrix (ECM) proteins noted in rodents in mid-
pregnancy support a role for ECM in regulating mechanical signals that may regulate phenotypic changes in
the myometrial cell. The focus of this application is to understand the regulatory role of myometrial ECM
structure on myometrial cell phenotype and function in pregnancy. With this goal in mind, we will study the role
and regulation of lysyl oxidase (LOX), a key enzyme that targets the ECM components collagen and elastic
fibers to regulate the stiffness and strength of the ECM. We provide evidence that 1) LOX expression is
temporally induced in the mouse myometrium in the synthetic phase (gestation days12 and 15) of myometrial
remodeling; 2) inhibition of LOX activity in pregnancy prevents onset of parturition and prevents the induction
of contraction associated genes such as connexin 43, oxytocin receptor and prostaglandin endoperoxide
synthase 2. We will determine if LOX regulates structural changes in the ECM and functional changes in the
myometrium that result in increased strength of the myometrium during the synthetic phase of remodeling. We
will also investigate whether LOX-mediated increases in tissue stiffness provides a mechanical signal that is
required to transition myometrial cells from quiescence in the synthetic phase to a contractile cell at term.
These studies will broaden our understanding of the mechanical signals that regulate the balance between
uterine quiescence and contractility and thus lead to identification of therapeutic targets for prevention of
premature uterine contractions and preterm birth. In addition these studies will integrate the varied expertise of
the applicant and provide the requisite training and career development required for his successful
development of a strong independent research program that will address an important and understudied area
of uterine biology.

## Key facts

- **NIH application ID:** 10115771
- **Project number:** 5R00HD090301-04
- **Recipient organization:** UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
- **Principal Investigator:** Shanmugasundaram Nallasamy
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $244,915
- **Award type:** 5
- **Project period:** 2019-11-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10115771

## Citation

> US National Institutes of Health, RePORTER application 10115771, Mechanisms by which the myometrial ECM modulates myometrial cell function (5R00HD090301-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10115771. Licensed CC0.

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