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Elastogenesis Correlates With Pigment Production in Murine Aortic Valve Leaflets.

ABSTRACT: Objective: Aortic valve (AV) leaflets rely on a precise extracellular matrix (ECM) microarchitecture for appropriate biomechanical performance. The ECM structure is maintained by valvular interstitial cells (VICs), which reside within the leaflets. The presence of pigment produced by a melanocytic population of VICs in mice with dark coats has been generally regarded as a nuisance, as it interferes with histological analysis of the AV leaflets. However, our previous studies have shown that the presence of pigment correlates with increased mechanical stiffness within the leaflets as measured by nanoindentation analyses. In the current study, we seek to better characterize the phenotype of understudied melanocytic VICs, explore the role of these VICs in ECM patterning, and assess the presence of these VICs in human aortic valve tissues. Approach and Results: Immunofluorescence and immunohistochemistry revealed that melanocytes within murine AV leaflets express phenotypic markers of either neuronal or glial cells. These VIC subpopulations exhibited regional patterns that corresponded to the distribution of elastin and glycosaminoglycan ECM proteins, respectively. VICs with neuronal and glial phenotypes were also found in human AV leaflets and showed ECM associations similar to those observed in murine leaflets. A subset of VICs within human AV leaflets also expressed dopachrome tautomerase, a common melanocyte marker. A spontaneous mouse mutant with no aortic valve pigmentation lacked elastic fibers and had reduced elastin gene expression within AV leaflets. A hyperpigmented transgenic mouse exhibited increased AV leaflet elastic fibers and elastin gene expression. Conclusions: Melanocytic VIC subpopulations appear critical for appropriate elastogenesis in mouse AVs, providing new insight into the regulation of AV ECM homeostasis. The identification of a similar VIC population in human AVs suggests conservation across species.

SUBMITTER: Hutcheson JD

PROVIDER: S-EPMC8257952 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Residual and physiological functional strains in soft tissues are known to play an important role in modulating organ stress distributions. Yet, no known comprehensive information on residual strains exist, or non-invasive techniques to quantify in-vivo deformations for the aortic valve (AV) leaflets. Herein we present a completely non-invasive approach for determining heterogeneous strains - both functional and residual - in semilunar valves and apply it to normal human AV leaflets. Transesophageal 3D echocardiographic (3DE) images of the AV were acquired from open-heart transplant patients, with each AV leaflet excised after heart explant and then imaged in a flattened configuration ex-vivo. Using an established spline parameterization of both 3DE segmentations and digitized ex-vivo images (Aggarwal et al., 2014), surface strains were calculated for deformation between the ex-vivo and three in-vivo configurations: fully open, just-coapted, and fully-loaded. Results indicated that leaflet area increased by an average of 20% from the ex-vivo to in-vivo open states, with a highly heterogeneous strain field. The increase in area from open to just-coapted state was the highest at an average of 25%, while that from just-coapted to fully-loaded remained almost unaltered. Going from the ex-vivo to in-vivo mid-systole configurations, the leaflet area near the basal attachment shrank slightly, whereas the free edge expanded by ~10%. This was accompanied by a 10° -20° shear along the circumferential-radial direction. Moreover, the principal stretches aligned approximately with the circumferential and radial directions for all cases, with the highest stretch being along the radial direction. Collectively, these results indicated that even though the AV did not support any measurable pressure gradient in the just-coapted state, the leaflets were significantly pre-strained with respect to the excised state. Furthermore, the collagen fibers of the leaflet were almost fully recruited in the just-coapted state, making the leaflet very stiff with marginal deformation under full pressure. Lastly, the deformation was always higher in the radial direction and lower along the circumferential one, the latter direction made stiffer by the preferential alignment of collagen fibers. These results provide significant insight into the distribution of residual strains and the in-vivo strains encountered during valve opening and closing in AV leaflets, and will form an important component of the tool that can evaluate valve׳s functional properties in a non-invasive manner.

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Elastogenesis Correlates With Pigment Production in Murine Aortic Valve Leaflets.

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