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.
Highlights
The aortic valve (AV) controls unidirectional blood flow from the left ventricle of the heart to the aorta for systemic circulation [1]
We recently reported the presence of glial markers in human AV leaflets [14]
We demonstrate that neuronal and glial valvular interstitial cells (VICs) within human AV leaflets express a melanocyte phenotypic marker
Summary
The aortic valve (AV) controls unidirectional blood flow from the left ventricle of the heart to the aorta for systemic circulation [1]. Both congenital aortic valve malformations and adult onset aortic valve disease significantly contribute to cardiovascular morbidity, but an incomplete understanding of the factors that govern valve function, including the active cellular contributions to valvular homeostasis, has hindered the development of treatment options [2]. A precise ECM microarchitecture of the AV leaflets dictates appropriate valvular function [3]. No previous reports exist on the role of VIC subpopulations in the production of specific ECM components within the aortic valve microarchitecture
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