Dynamic Expression Profiles of Sox9 in Embryonic, Post Natal, and Adult Heart Valve Cell Populations

Gallina, Donika; Lincoln, Joy

doi:10.1002/ar.23913

Cited by 11 publications

(12 citation statements)

References 38 publications

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“…We found that SOX9 was expressed in a few aortic VECs (Figure 6A, arrows) and weakly in the VICs (Figure 6A, arrowheads) of adult control mice as previously reported. 43 In contrast, SOX9 was strongly upregulated in the VICs of Prox1 ∆VEC mice (Figure 6A). SOX9 expression was also significantly upregulated in the aortic VICs of 6-month-old Tie2-Cre; Pdgfrb +/LSL-D849V mice (Figure 6B).…”

Section: Resultsmentioning

confidence: 95%

PROX1 Inhibits PDGF-B Expression to Prevent Myxomatous Degeneration of Heart Valves

Ho,

Geng,

O’Donnell

et al. 2023

Circulation Research

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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 Prox1 ΔVEC 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 Prox1 ΔVEC mice become progressively thick and myxomatous. Echocardiography revealed that the aortic valves of Prox1 ΔVEC mice are stenotic . FOXC2 was downregulated and PDGF-B (platelet-derived growth factor-B) was upregulated in the VECs of Prox1 ΔVEC mice. Conditional knockdown of FOXC2 and conditional overexpression of PDGF-B in VECs recapitulated the phenotype of Prox1 ΔVEC 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 Prox1 ΔVEC mice. Conclusions: PROX1 antagonizes PDGF-B signaling partially via FOXC2 to maintain the extracellular matrix composition and prevent myxomatous degeneration of cardiac valves.

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Section: Resultsmentioning

confidence: 95%

PROX1 Inhibits PDGF-B Expression to Prevent Myxomatous Degeneration of Heart Valves

Ho,

Geng,

O’Donnell

et al. 2023

Circulation Research

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“…Recent work in mice demonstrated that following EMT, mesenchymal cells activate expression of the Sox9 transcription factor in the population of cells that differentiate as VICs [36]. In embryonic stages, Sox9 is not expressed in VECs, and thus may provide a genetic handle to identify additional genes required for VIC differentiation.…”

Section: Mesenchymal Cells Populate the Endocardial Cushionsmentioning

confidence: 99%

“…A critical role for Sox9 in proliferation of valve precursor cells was suggested by targeted loss of function mice, which display severely hypoblastic endocardial cushions [37]. Sox9 has later embryonic roles in ECM remodeling later in valve development, and following birth, becomes expressed in VECs as well as maturing VICs [36].…”

Section: Mesenchymal Cells Populate the Endocardial Cushionsmentioning

confidence: 99%

Biomechanical Cues Direct Valvulogenesis

Ahuja

Ostwald

Bark

et al. 2020

JCDD

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The vertebrate embryonic heart initially forms with two chambers, a ventricle and an atrium, separated by the atrioventricular junction. Localized genetic and biomechanical information guides the development of valves, which function to ensure unidirectional blood flow. If the valve development process goes awry, pathology associated with congenital valve defects can ensue. Congenital valve defects (CVD) are estimated to affect 1–2% of the population and can often require a lifetime of treatment. Despite significant clinical interest, molecular genetic mechanisms that direct valve development remain incompletely elucidated. Cells in the developing valve must contend with a dynamic hemodynamic environment. A growing body of research supports the idea that cells in the valve are highly sensitive to biomechanical forces, which cue changes in gene expression required for normal development or for maintenance of the adult valve. This review will focus on mechanotransductive pathways involved in valve development across model species. We highlight current knowledge regarding how cells sense physical forces associated with blood flow and pressure in the forming heart, and summarize how these changes are transduced into genetic and developmental responses. Lastly, we provide perspectives on how altered biomechanical cues may lead to CVD pathogenesis.

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“…Implantation of bFGF under the skin of mice can induce angiogenesis. Due to the high-water content in the gel, the degradation rate is fast, the release of bFGF is fast, and the induction time of angiogenesis is very short (9). Wiktor transplanted bFGF hydrogel under the skin of mice and observed the formation of new blood vessels around the implant.…”

Section: Introductionmentioning

confidence: 99%

Effect of bFGF gel nano-sustained-release technology on rehabilitation effect of adult heart valve replacement

Huang

Wang

Cheng-yong

et al. 2022

Cell Mol Biol (Noisy-le-grand)

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the Due to the rapid improvement of economic level, aging and lifestyle changes, the incidence of valvular heart disease continues to increase, and the bFGF gel nano sustained-release technology plays an important role in the rehabilitation of adult heart valve replacement patients. The purpose of this article is to investigate the effect of bFGF gel nano-slow release technology on the rehabilitation effect of adult heart valve replacement patients. The research object was selected from all cases of valve replacement surgery from January 2019 to January 2020, and 216 patients were divided into experimental group and control group, the experimental group carried out the sustained release of bFGF gel nanospheres. The experimental group was 49.76±8.13 years old, including 94 cases of rheumatic heart disease, 13 cases of degenerative valvular disease, and 3 cases of congenital valvular disease, a total of 110 cases. Heart performance tests were performed respectively. The results showed that the incidence of atrial fibrillation, left ventricular hypertrophy and ST-segment depression of 0.1m V in the experimental group were 32.19%, 34.48%, and 19.84%, while the corresponding data in the control group were 62.78%, 52.07%, and 45.87%. It can be seen that bFGF gel nano sustained-release technology is of great significance for the rehabilitation of adult heart valve replacement patients.

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Dynamic Expression Profiles of Sox9 in Embryonic, Post Natal, and Adult Heart Valve Cell Populations

Cited by 11 publications

References 38 publications

PROX1 Inhibits PDGF-B Expression to Prevent Myxomatous Degeneration of Heart Valves

PROX1 Inhibits PDGF-B Expression to Prevent Myxomatous Degeneration of Heart Valves

Biomechanical Cues Direct Valvulogenesis

Effect of bFGF gel nano-sustained-release technology on rehabilitation effect of adult heart valve replacement

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