# Flow and endothelial signaling in acquired myxomatous valve disease

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $725,845

## Abstract

Project Summary
Myxomatous valve disease (MVD) arises in 2-3% of the human population and causes
mitral valve prolapse and regurgitation. Although rare inherited forms of MVD have been
identified, most cases arise in previously healthy valves in older individuals. MVD is
characterized by proliferation of valve interstitial cells (VICs), increased matrix
production, and TGFb signaling, but how such changes arise in previously healthy
valves is unknown. We have recently demonstrated that hemodynamic shear forces
direct heart valve development through expression of the flow-regulated KLF2 and KLF4
transcription factors in valve endothelial cells (VECs), but whether and how the
hemodynamic environment might regulate the function of the mature heart valve has not
been addressed. Our preliminary studies reveal that inducible genetic loss of KLF2 and
KLF4 in mature VECs results in a MVD phenotype associated with high VEC and VIC
proliferation, increased matrix deposition, and evidence of pathologic endothelial-
mesenchymal transition (EndMT). Importantly, we find that similar MVD pathology is
conferred by loss of blood flow across the mitral valve of transplanted hearts. These
findings support a novel mechanism for MVD in which changes in hemodynamic
conditions that alter VEC KLF2/4 expression give rise to acquired MVD. This proposal
will test this hemodynamic mechanism for MVD using new genetic tools to examine how
blood flow and KLF2/4 in VECs control the cellular biology (Aim 1) and the matrix biology
(Aim 2) of the mature valve. The proposed studies are expected to provide new insight
into MVD pathogenesis, the role of blood flow in adult heart valve homeostasis, and the
role of pathologic EndMT in the cardiovascular disease.

## Key facts

- **NIH application ID:** 10033435
- **Project number:** 1R01HL153224-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** MARK L KAHN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $725,845
- **Award type:** 1
- **Project period:** 2020-08-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10033435

## Citation

> US National Institutes of Health, RePORTER application 10033435, Flow and endothelial signaling in acquired myxomatous valve disease (1R01HL153224-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10033435. Licensed CC0.

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