# Endothelial subpopulations in heart valve development and congenital heart disease

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2021 · $485,084

## Abstract

Endothelial Subpopulations in Heart Valve Development and Congenital Disease
Project Summary
 Normal heart valve structure and composition are established during development, and congenital
valve malformations, such as those arising from mutations in structural protein genes as in Marfan syndrome
(MFS), have progressive disorganization and dysfunction over time. Myxomatous valve disease (MVD) is
characterized by thickening and progressive degeneration of valve leaflets, leading to valvular regurgitation
and reduced heart function. While fluctuating mechanical forces related to blood flow act on the valve leaflets
in development and disease, it is not known how these forces affect valve structure and function at the
molecular level. Single cell RNA sequencing (scRNAseq) demonstrated valve endothelial cell (VEC)
subpopulations localized in regions of heart valve leaflets with distinct blood flow profiles. One of these VEC
subpopulations expresses Prox1, a mechanosensitive transcription factor, but its roles in heart valve
development, homeostasis, and disease are unknown. Moreover, Prox1 expression is expanded to the
laminar flow side of myxomatous valves in a mouse model of MFS with reported valve regurgitation. We
hypothesize that Prox1 expression in heart VECs, subject to Wnt/β-catenin activation, is critical for valve
leaflet organization during development and for maintenance of valve structure and ECM organization in
adults. The Aims are: 1) Determine the requirements for Prox1 in heart valve development and homeostasis.
2) Determine if Prox1 mislocalization in myxomatous valve leaflets contributes to macrophage infiltration and
MVD progression. 3) Determine if Wnt/beta-catenin signaling in valve endothelial cells is required for localized
Prox1 expression and endothelial junction maturation. The long-term goals of these studies are to define
mechanosensitive regulatory mechanisms of heart valve development and pathologic remodeling, thus
leading to the development of new nonsurgical therapeutic approaches for myxomatous valve disease.

## Key facts

- **NIH application ID:** 10132030
- **Project number:** 1R01HL156270-01
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Katherine E Yutzey
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $485,084
- **Award type:** 1
- **Project period:** 2020-12-15 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10132030

## Citation

> US National Institutes of Health, RePORTER application 10132030, Endothelial subpopulations in heart valve development and congenital heart disease (1R01HL156270-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10132030. Licensed CC0.

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