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.
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:84543 |
| Date | 04 April 2023 |
| Creators | Hutcheson, Joshua D., Schlotter, Florian, Creager, Michael D., Li, Xiaoshuang, Pham, Tan, Vyas, Payal, Higashi, Hideyuki, Body, Simon C., Aikawa, Masanori, Singh, Sasha A., Kos, Lidia, Aikawa, Elena |
| Publisher | Frontiers Research Foundation |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, doc-type:article, info:eu-repo/semantics/article, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 2297-055X, 678401 |
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