# Novel lymphatic genes that regulate heart valve development and disease

> **NIH NIH R01** · OKLAHOMA MEDICAL RESEARCH FOUNDATION · 2024 · $530,463

## Abstract

PROJECT SUMMARY/ABSTRACT
Valves are present within hearts, veins and lymphatic vessels to regulate the flow of blood and lymph. Defects
in the development or functioning of valves could lead to diseases such as lymphedema and degenerative heart
valve disease. Venous and lymphatic (vascular) valves are composed of two layers of endothelial cells with a
thin layer of collagen-rich extra cellular matrix (ECM). Few if any interstitial cells are observed within vascular
valves. In contrast, cardiac valves are made of two major cell types: numerous ECM producing valvular interstitial
cells (VICs), which are surrounded by a single layer of valvular endothelial cells (VECs). Despite significant
differences in their structure and the mechanical force that they experience, cardiac and vascular valves share
interesting similarities. The homeobox transcription factor PROX1 is necessary for the development of vascular
valves. PROX1 is also expressed in a subset of VECs on the downstream side of heart valves. We have now
determined that the deletion of PROX1 from VECs results in the accumulation of proteoglycans and the
consequent thickening of heart valves. Thus, PROX1 in VECs regulates the development and functioning of
VICs through yet unknown mechanisms.
Building on our preliminary data we will test our Central Hypothesis that a previously unknown
PROX1àFOXC2àPDGF-B signaling pathway from downstream VECs regulates VIC identity and, in turn, the
ECM composition of valves.
Abnormally high synthesis of proteoglycans is observed in several valve disorders. Valve defects are
observed in ~8% in individuals >65 years old and ~13% in those who are >75. Pharmacological approaches to
treat these valve defects do not exist. Hence, the outcomes of our proposed research are expected to be
significant because they will substantially advance our insight into the molecular and cellular mechanisms of
VEC-VIC crosstalk during cardiac valve development and shed light on potential therapeutic strategies.

## Key facts

- **NIH application ID:** 10754947
- **Project number:** 5R01HL163095-02
- **Recipient organization:** OKLAHOMA MEDICAL RESEARCH FOUNDATION
- **Principal Investigator:** Rajanarayanan S Srinivasan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $530,463
- **Award type:** 5
- **Project period:** 2022-12-15 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10754947

## Citation

> US National Institutes of Health, RePORTER application 10754947, Novel lymphatic genes that regulate heart valve development and disease (5R01HL163095-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10754947. Licensed CC0.

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