TY - JOUR
T1 - PROX1 Inhibits PDGF-B Expression to Prevent Myxomatous Degeneration of Heart Valves
AU - Ho, Yen Chun
AU - Geng, Xin
AU - O'Donnell, Anna
AU - Ibarrola, Jaime
AU - Fernandez-Celis, Amaya
AU - Varshney, Rohan
AU - Subramani, Kumar
AU - Azartash-Namin, Zheila J.
AU - Kim, Jang
AU - Silasi, Robert
AU - Wylie-Sears, Jill
AU - Alvandi, Zahra
AU - Chen, Lijuan
AU - Cha, Boksik
AU - Chen, Hong
AU - Xia, Lijun
AU - Zhou, Bin
AU - Lupu, Florea
AU - Burkhart, Harold M.
AU - Aikawa, Elena
AU - Olson, Lorin E.
AU - Ahamed, Jasimuddin
AU - López-Andrés, Natalia
AU - Bischoff, Joyce
AU - Yutzey, Katherine E.
AU - Srinivasan, R. Sathish
N1 - Publisher Copyright:
© 2023 The Authors.
PY - 2023/9/1
Y1 - 2023/9/1
N2 - BACKGROUND: Cardiac valve disease is observed in 2.5% of the general population and 10% of the elderly people. Effective pharmacological treatments are currently not available, and patients with severe cardiac valve disease require surgery. PROX1 (prospero-related homeobox transcription factor 1) and FOXC2 (Forkhead box C2 transcription factor) are transcription factors that are required for the development of lymphatic and venous valves. We found that PROX1 and FOXC2 are expressed in a subset of valvular endothelial cells (VECs) that are located on the downstream (fibrosa) side of cardiac valves. Whether PROX1 and FOXC2 regulate cardiac valve development and disease is not known. METHODS: We used histology, electron microscopy, and echocardiography to investigate the structure and functioning of heart valves from Prox1ΔVEC mice in which Prox1 was conditionally deleted from VECs. Isolated valve endothelial cells and valve interstitial cells were used to identify the molecular mechanisms in vitro, which were tested in vivo by RNAScope, additional mouse models, and pharmacological approaches. The significance of our findings was tested by evaluation of human samples of mitral valve prolapse and aortic valve insufficiency. RESULTS: Histological analysis revealed that the aortic and mitral valves of Prox1ΔVEC mice become progressively thick and myxomatous. Echocardiography revealed that the aortic valves of Prox1ΔVEC mice are stenotic. FOXC2 was downregulated and PDGF-B (platelet-derived growth factor-B) was upregulated in the VECs of Prox1ΔVEC mice. Conditional knockdown of FOXC2 and conditional overexpression of PDGF-B in VECs recapitulated the phenotype of Prox1ΔVEC mice. PDGF-B was also increased in mice lacking FOXC2 and in human mitral valve prolapse and insufficient aortic valve samples. Pharmacological inhibition of PDGF-B signaling with imatinib partially ameliorated the valve defects of Prox1ΔVEC mice. CONCLUSIONS: PROX1 antagonizes PDGF-B signaling partially via FOXC2 to maintain the extracellular matrix composition and prevent myxomatous degeneration of cardiac valves.
AB - BACKGROUND: Cardiac valve disease is observed in 2.5% of the general population and 10% of the elderly people. Effective pharmacological treatments are currently not available, and patients with severe cardiac valve disease require surgery. PROX1 (prospero-related homeobox transcription factor 1) and FOXC2 (Forkhead box C2 transcription factor) are transcription factors that are required for the development of lymphatic and venous valves. We found that PROX1 and FOXC2 are expressed in a subset of valvular endothelial cells (VECs) that are located on the downstream (fibrosa) side of cardiac valves. Whether PROX1 and FOXC2 regulate cardiac valve development and disease is not known. METHODS: We used histology, electron microscopy, and echocardiography to investigate the structure and functioning of heart valves from Prox1ΔVEC mice in which Prox1 was conditionally deleted from VECs. Isolated valve endothelial cells and valve interstitial cells were used to identify the molecular mechanisms in vitro, which were tested in vivo by RNAScope, additional mouse models, and pharmacological approaches. The significance of our findings was tested by evaluation of human samples of mitral valve prolapse and aortic valve insufficiency. RESULTS: Histological analysis revealed that the aortic and mitral valves of Prox1ΔVEC mice become progressively thick and myxomatous. Echocardiography revealed that the aortic valves of Prox1ΔVEC mice are stenotic. FOXC2 was downregulated and PDGF-B (platelet-derived growth factor-B) was upregulated in the VECs of Prox1ΔVEC mice. Conditional knockdown of FOXC2 and conditional overexpression of PDGF-B in VECs recapitulated the phenotype of Prox1ΔVEC mice. PDGF-B was also increased in mice lacking FOXC2 and in human mitral valve prolapse and insufficient aortic valve samples. Pharmacological inhibition of PDGF-B signaling with imatinib partially ameliorated the valve defects of Prox1ΔVEC mice. CONCLUSIONS: PROX1 antagonizes PDGF-B signaling partially via FOXC2 to maintain the extracellular matrix composition and prevent myxomatous degeneration of cardiac valves.
KW - aortic valve
KW - endothelial cells
KW - extracellular matrix
KW - mitral valve
KW - prolapse
UR - http://www.scopus.com/inward/record.url?scp=85169503566&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85169503566&partnerID=8YFLogxK
U2 - 10.1161/CIRCRESAHA.123.323027
DO - 10.1161/CIRCRESAHA.123.323027
M3 - Article
C2 - 37555328
AN - SCOPUS:85169503566
SN - 0009-7330
VL - 133
SP - 463
EP - 480
JO - Circulation research
JF - Circulation research
IS - 6
ER -
