Elastogenesis Correlates With Pigment Production in Murine Aortic Valve Leaflets

Hutcheson, Joshua D.; Schlotter, Florian; Creager, Michael; Li, Xiaoshuang; Pham, Tan; Vyas, Payal; Higashi, Hideyuki; Body, Simon C.; Aikawa, Masanori; Singh, Sasha A; Kos, Lidia; Aikawa, Elena

doi:10.3389/fcvm.2021.678401

Cited by 6 publications

(5 citation statements)

References 26 publications

(33 reference statements)

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“…The addition of albino mice indicate that pigment production-rather than the presence of melanocytic populations-lead to the observed changes in elastic fiber patterning. We also found that elastic fibers in the WT leaflets were orthogonal to the collagen fibers, similar to the alignment known in human AoV (4,18). While not significantly different, we observed trends that indicate less orthogonality in the K5-Edn3 and Kit Wv elastic fibers.…”

Section: Discussionsupporting

confidence: 80%

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Pigmentation Affects Elastic Fiber Patterning and Biomechanical Behavior of the Murine Aortic Valve

Nasim

Pandey

Kanashiro‐Takeuchi

et al. 2021

Front. Cardiovasc. Med.

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The aortic valve (AoV) maintains unidirectional blood distribution from the left ventricle of the heart to the aorta for systemic circulation. The AoV leaflets rely on a precise extracellular matrix microarchitecture of collagen, elastin, and proteoglycans for appropriate biomechanical performance. We have previously demonstrated a relationship between the presence of pigment in the mouse AoV with elastic fiber patterning using multiphoton imaging. Here, we extended those findings using wholemount confocal microscopy revealing that elastic fibers were diminished in the AoV of hypopigmented mice (KitWv and albino) and were disorganized in the AoV of K5-Edn3 transgenic hyperpigmented mice when compared to wild type C57BL/6J mice. We further used atomic force microscopy to measure stiffness differences in the wholemount AoV leaflets of mice with different levels of pigmentation. We show that AoV leaflets of K5-Edn3 had overall higher stiffness (4.42 ± 0.35 kPa) when compared to those from KitWv (2.22 ± 0.21 kPa), albino (2.45 ± 0.16 kPa), and C57BL/6J (3.0 ± 0.16 kPa) mice. Despite the striking elastic fiber phenotype and noted stiffness differences, adult mutant mice were found to have no overt cardiac differences as measured by echocardiography. Our results indicate that pigmentation, but not melanocytes, is required for proper elastic fiber organization in the mouse AoV and dictates its biomechanical properties.

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Section: Discussionsupporting

confidence: 80%

“…The inner layers of VICs are responsible for producing and maintaining the ECM. The VICs comprise a heterogeneous population of cells that include smooth muscle cells, fibroblasts, myofibroblasts, neurons and glia (4,5). Besides these subpopulations of VICs, murine heart valves contain melanin producing cells, the melanocytes (6).…”

Section: Introductionmentioning

confidence: 99%

Pigmentation Affects Elastic Fiber Patterning and Biomechanical Behavior of the Murine Aortic Valve

Nasim

Pandey

Kanashiro‐Takeuchi

et al. 2021

Front. Cardiovasc. Med.

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“…SYBR Green-based (Thermo Fisher Scientific# 4385612) quantitative real-time (RT) PCR was performed to calculate mean relative gene expression after normalization of C t values to glyceraldehyde 3-phosphate dehydrogenase ( GAPDH ) using the ΔΔ Ct method. GAPDH has previously been utilized as a control gene for normalization in aortic valve leaflets ( 40 ). All primer sequences are provided in Supplementary Data 2 .…”

Section: Methodsmentioning

confidence: 99%

Single-cell RNA-sequencing analysis of aortic valve interstitial cells demonstrates the regulation of integrin signaling by nitric oxide

Majumdar

Choudhury

Manivannan

et al. 2022

Front. Cardiovasc. Med.

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Calcific aortic valve disease (CAVD) is an increasingly prevalent condition among the elderly population that is associated with significant morbidity and mortality. Insufficient understanding of the underlying disease mechanisms has hindered the development of pharmacologic therapies for CAVD. Recently, we described nitric oxide (NO) mediated S-nitrosylation as a novel mechanism for preventing the calcific process. We demonstrated that NO donor or an S-nitrosylating agent, S-nitrosoglutathione (GSNO), inhibits spontaneous calcification in porcine aortic valve interstitial cells (pAVICs) and this was supported by single-cell RNA sequencing (scRNAseq) that demonstrated NO donor and GSNO inhibited myofibroblast activation of pAVICs. Here, we investigated novel signaling pathways that are critical for the calcification of pAVICs that are altered by NO and GSNO by performing an in-depth analysis of the scRNA-seq dataset. Transcriptomic analysis revealed 1,247 differentially expressed genes in pAVICs after NO donor or GSNO treatment compared to untreated cells. Pathway-based analysis of the differentially expressed genes revealed an overrepresentation of the integrin signaling pathway, along with the Rho GTPase, Wnt, TGF-β, and p53 signaling pathways. We demonstrate that ITGA8 and VCL, two of the identified genes from the integrin signaling pathway, which are known to regulate cell-extracellular matrix (ECM) communication and focal adhesion, were upregulated in both in vitro and in vivo calcific conditions. Reduced expression of these genes after treatment with NO donor suggests that NO inhibits calcification by targeting myofibroblast adhesion and ECM remodeling. In addition, withdrawal of NO donor after 3 days of exposure revealed that NO-mediated transcriptional and translational regulation is a transient event and requires continuous NO exposure to inhibit calcification. Overall, our data suggest that NO and S-nitrosylation regulate the integrin signaling pathway to maintain healthy cell-ECM interaction and prevent CAVD.

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“…116 Murine aortic valves contain pigment-producing melanocytes, 117 which are easily confused for positive von Kossa staining (which identifies calcium deposits) because both appear as brown precipitates. Melanocytes in VICs help to produce the elastin of the leaflet 118,119 ; whether a similar population exists in humans in unknown. Ovine, porcine, and bovine models better recapitulate the CAVD observed in humans, but large-animal models entail high cost and space requirements.…”

Section: Congenital Bicuspid and Unicuspid Valvesmentioning

confidence: 99%

Unraveling the Mechanisms of Valvular Heart Disease to Identify Medical Therapy Targets: A Scientific Statement From the American Heart Association

Small,

Yutzey,

Binstadt

et al. 2024

Circulation

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Valvular heart disease is a common cause of morbidity and mortality worldwide and has no effective medical therapy. Severe disease is managed with valve replacement procedures, which entail high health care–related costs and postprocedural morbidity and mortality. Robust ongoing research programs have elucidated many important molecular pathways contributing to primary valvular heart disease. However, there remain several key challenges inherent in translating research on valvular heart disease to viable molecular targets that can progress through the clinical trials pathway and effectively prevent or modify the course of these common conditions. In this scientific statement, we review the basic cellular structures of the human heart valves and discuss how these structures change in primary valvular heart disease. We focus on the most common primary valvular heart diseases, including calcific aortic stenosis, bicuspid aortic valves, mitral valve prolapse, and rheumatic heart disease, and outline the fundamental molecular discoveries contributing to each. We further outline potential therapeutic molecular targets for primary valvular heart disease and discuss key knowledge gaps that might serve as future research priorities.

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Elastogenesis Correlates With Pigment Production in Murine Aortic Valve Leaflets

Cited by 6 publications

References 26 publications

Pigmentation Affects Elastic Fiber Patterning and Biomechanical Behavior of the Murine Aortic Valve

Pigmentation Affects Elastic Fiber Patterning and Biomechanical Behavior of the Murine Aortic Valve

Single-cell RNA-sequencing analysis of aortic valve interstitial cells demonstrates the regulation of integrin signaling by nitric oxide

Unraveling the Mechanisms of Valvular Heart Disease to Identify Medical Therapy Targets: A Scientific Statement From the American Heart Association

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