Collagen Fibrillogenesis in the Mitral Valve: It’s a Matter of Compliance

Goodwin, Richard L.; Kheradvar, Arash; Norris, Russell A.; Price, Robert L.; Potts, Jay D.

doi:10.3390/jcdd8080098

Cited by 4 publications

(3 citation statements)

References 32 publications

(42 reference statements)

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“…27 This finding supports the observed decreased valve thickness in MAZ51-treated valves as it is known that valve thickening is partially due to increased collagen production. 24,28 Indeed, we found that the area of positive collagen staining decreased only in MAZ51-treated valves (Figure S12D) and collagen area significantly correlated with valve thickness (Figure S12E). These findings demonstrate that VEGF-C-VEGFR3 signaling is important for the growth and/or maintenance of lymphatic vessels in the inflamed valve during peak inflammation, but loss of these lymphatics during that time frame does not directly affect valve disease progression.…”

Section: Vegf-c-vegfr3 Signaling Regulates Lymphatic Outgrowth In The...mentioning

confidence: 88%

Profibrotic VEGFR3-Dependent Lymphatic Vessel Growth in Autoimmune Valvular Carditis

Osinski,

Yellamilli,

Firulyova

et al. 2024

ATVB

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BACKGROUND: Rheumatic heart disease is the major cause of valvular heart disease in developing nations. Endothelial cells (ECs) are considered crucial contributors to rheumatic heart disease, but greater insight into their roles in disease progression is needed. METHODS: We used a Cdh5 -driven EC lineage-tracing approach to identify and track ECs in the K/B.g7 model of autoimmune valvular carditis. Single-cell RNA sequencing was used to characterize the EC populations in control and inflamed mitral valves. Immunostaining and conventional histology were used to evaluate lineage tracing and validate single-cell RNA-sequencing findings. The effects of VEGFR3 (vascular endothelial growth factor receptor 3) and VEGF-C (vascular endothelial growth factor C) inhibitors were tested in vivo. The functional impact of mitral valve disease in the K/B.g7 mouse was evaluated using echocardiography. Finally, to translate our findings, we analyzed valves from human patients with rheumatic heart disease undergoing mitral valve replacements. RESULTS: Lineage tracing in K/B.g7 mice revealed new capillary lymphatic vessels arising from valve surface ECs during the progression of disease in K/B.g7 mice. Unsupervised clustering of mitral valve single-cell RNA-sequencing data revealed novel lymphatic valve ECs that express a transcriptional profile distinct from other valve EC populations including the recently identified PROX1 (Prospero homeobox protein 1)+ lymphatic valve ECs. During disease progression, these newly identified lymphatic valve ECs expand and upregulate a profibrotic transcriptional profile. Inhibiting VEGFR3 through multiple approaches prevented expansion of this mitral valve lymphatic network. Echocardiography demonstrated that K/B.g7 mice have left ventricular dysfunction and mitral valve stenosis. Valve lymphatic density increased with age in K/B.g7 mice and correlated with worsened ventricular dysfunction. Importantly, human rheumatic valves contained similar lymphatics in greater numbers than nonrheumatic controls. CONCLUSIONS: These studies reveal a novel mode of inflammation-associated, VEGFR3-dependent postnatal lymphangiogenesis in murine autoimmune valvular carditis, with similarities to human rheumatic heart disease.

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Section: Vegf-c-vegfr3 Signaling Regulates Lymphatic Outgrowth In The...mentioning

confidence: 88%

Profibrotic VEGFR3-Dependent Lymphatic Vessel Growth in Autoimmune Valvular Carditis

Osinski,

Yellamilli,

Firulyova

et al. 2024

ATVB

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“…Collagen fibers are the main contributor to the structural integrity and mechanical competency of MVL 17 – 19 . In DMVD, MVL is associated with a disrupted microstructure of collagen fibers 8 , 12 , 15 , 16 .…”

Section: Discussionmentioning

confidence: 99%

“…Among the components of the extracellular matrix, collagen is the most important as it is the main mechanical contributor to the proper functioning of mitral valve leaflets (MVL) 17 – 19 . A disruption of the collagen network leads to significantly altered biomechanics and consequently malfunction of the mitral valve leaflet.…”

Section: Introductionmentioning

confidence: 99%

Quantified planar collagen distribution in healthy and degenerative mitral valve: biomechanical and clinical implications

Sadeghinia,

Persson,

Ellensen

et al. 2024

Sci Rep

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Degenerative mitral valve disease is a common valvular disease with two arguably distinct phenotypes: fibroelastic deficiency and Barlow’s disease. These phenotypes significantly alter the microstructures of the leaflets, particularly the collagen fibers, which are the main mechanical load carriers. The predominant method of investigation is histological sections. However, the sections are cut transmurally and provide a lateral view of the microstructure of the leaflet, while the mechanics and function are determined by the planar arrangement of the collagen fibers. This study, for the first time, quantitatively examined planar collagen distribution quantitatively in health and disease using second harmonic generation microscopy throughout the thickness of the mitral valve leaflets. Twenty diseased samples from eighteen patients and six control samples were included in this study. Healthy tissue had highly aligned collagen fibers. In fibroelastic deficiency they are less aligned and in Barlow’s disease they are completely dispersed. In both diseases, collagen fibers have two preferred orientations, which, in contrast to the almost constant one orientation in healthy tissues, also vary across the thickness. The results indicate altered in vivo mechanical stresses and strains on the mitral valve leaflets as a result of disease-related collagen remodeling, which in turn triggers further remodeling.

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The effects of leaflet material properties on the simulated function of regurgitant mitral valves

Ching

Sabin

et al. 2023

Journal of the Mechanical Behavior of Biomedical Materials

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Collagen Fibrillogenesis in the Mitral Valve: It’s a Matter of Compliance

Cited by 4 publications

References 32 publications

Profibrotic VEGFR3-Dependent Lymphatic Vessel Growth in Autoimmune Valvular Carditis

Profibrotic VEGFR3-Dependent Lymphatic Vessel Growth in Autoimmune Valvular Carditis

Quantified planar collagen distribution in healthy and degenerative mitral valve: biomechanical and clinical implications

The effects of leaflet material properties on the simulated function of regurgitant mitral valves

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