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May 15, 2023Open Access

Deletion of Prox1 from valvular endothelial cells in mice resulted in enlarged, myxomatous, and stenotic valves, which was partially ameliorated by pharmacological inhibition of PDGF-B signaling.

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Why the study?

Effective pharmacological treatments for cardiac valve disease are lacking, and whether the transcription factors PROX1 and FOXC2 regulate cardiac valve development and disease was unknown.

Population

Prox1 ΔVEC mice, isolated valve cells, and human MVP and aortic valve insufficiency samples

Comparison

Prox1 conditional deletion and PDGF-B pathway modulation vs controls

Design

Preclinical animal and in vitro mechanistic study with human tissue validation

Key result

Deletion of Prox1 from valvular endothelial cells in mice resulted in enlarged, myxomatous, and stenotic valves, which was partially ameliorated by pharmacological inhibition of PDGF-B signaling.

Authors

YHYen‐Chun HoXGXin GengAOAnna O’Donnell

Discussion

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Member takes

Overview

PDGF-B inhibition merits testing in myxomatous valve disease; animal data leave human translation open.

Key Points

  • The study aims to investigate the regulatory role of PROX1 and FOXC2 in cardiac valve development and disease, specifically their interaction with PDGF-B.
  • Used histology, electron microscopy, and echocardiography on Prox1 ΔVEC mice to assess heart valve structure.
  • Isolated valvular endothelial cells for in vitro testing of molecular mechanisms.
  • Evaluated human mitral valve prolapse and aortic valve insufficiency samples for expression patterns of PROX1 and PDGF-B.
  • Aortic and mitral valves of Prox1 ΔVEC mice showed increased thickness and myxomatous features.
  • PDGF-B was significantly overexpressed in Prox1 ΔVEC mice and in human valve disease examples.
  • Inhibition of PDGF-B signaling with imatinib partially improved valve defects in Prox1 ΔVEC mice.

Structured PICO

P
Population
Prox1 ΔVEC mice (conditional deletion of Prox1 from valvular endothelial cells), isolated valve endothelial and interstitial cells, and human samples of mitral valve prolapse and aortic valve insufficiency
E
Exposure
Conditional deletion of Prox1, conditional knockdown of FOXC2, conditional overexpression of PDGF-B, and pharmacological inhibition of PDGF-B signaling with imatinib
C
Comparator
Control mice/cells
O
Outcome
Valve structure and function (thickness, myxomatous changes, stenosis) and molecular expression (FOXC2, PDGF-B)surrogate

PROX1 and FOXC2 inhibit PDGF-B expression to prevent myxomatous degeneration of heart valves, identifying PDGF-B as a potential therapeutic target for myxomatous valve disease.

Cite This Study

Ho et al. (2023) studied Cardiac valve disease (myxomatous degeneration). Prox1 deletion (Prox1 ΔVEC) vs. Wild-type/control was evaluated on Valve structure and function (myxomatous degeneration and stenosis). Deletion of Prox1 from valvular endothelial cells in mice resulted in enlarged, myxomatous, and stenotic valves, which was partially ameliorated by pharmacological inhibition of PDGF-B signaling.

synapsesocial.com/papers/6a201f4d76ec520ee9a1b125https://doi.org/10.1101/2023.05.10.540284
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Also Consider

Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context:

  1. 1PROX1 Inhibits PDGF-B Expression to Prevent Myxomatous Degeneration of Heart Valves2023 · 18 citations
  2. 2Prox1 maintains muscle structure and growth in the developing heart2008 · 133 citations
  3. 3Loss of Krox20 results in aortic valve regurgitation and impaired transcriptional activation of fibrillar collagen genes2014 · 30 citations
  4. 4Loss of Prox1 in striated muscle causes slow to fast skeletal muscle fiber conversion and dilated cardiomyopathy2014 · 54 citations
  5. 5Increased canonical WNT/β-catenin signalling and myxomatous valve disease2016 · 8 citations