title: Growth and maturation of heart valves leads to changes in endothelial cell distribution, impaired function, decreased metabolism and reduced cell proliferation.
abstract: Risk factors of heart valve disease are well defined and prolonged exposure throughout life leads to degeneration and dysfunction in up to 33% of the population. While aortic valve replacement remains the most common need for cardiovascular surgery particularly in those aged over 65, the underlying mechanisms of progressive deterioration are unknown. In other cardiovascular systems, a decline in endothelial cell integrity and function play a major role in promoting pathological changes, and while similar mechanisms have been speculated in the valves, studies to support this are lacking. The goal of this study was to examine age-related changes in valve endothelial cell (VEC) distribution, morphology, function and transcriptomes during critical stages of valve development (embryonic), growth (postnatal (PN)), maintenance (young adult) and aging (aging adult). Using a combination of in vivo mouse, and in vitro porcine assays we show that VEC function including, nitric oxide bioavailability, metabolism, endothelial-to-mesenchymal potential, membrane self-repair and proliferation decline with age. In addition, density of VEC distribution along the endothelium decreases and this is associated with changes in morphology, decreased cell-cell interactions, and increased permeability. These changes are supported by RNA-seq analysis showing that focal adhesion-, cell cycle-, and oxidative phosphorylation-associated biological processes are negatively impacted by aging. Furthermore, by performing high-throughput analysis we are able to report the differential and common transcriptomes of VECs at each time point that can provide insights into the mechanisms underlying age-related dysfunction. These studies suggest that maturation of heart valves over time is a multifactorial process and this study has identified several key parameters that may contribute to impairment of the valve to maintain critical structure-function relationships; leading to degeneration and disease.
authors.affiliation: Center for Cardiovascular Research, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA; The Heart Center, Nationwide Children's Hospital, Columbus, OH, USA; Department of Pediatrics, Ohio State University, Columbus, OH, USA.
authors.forename: Lindsey J
authors.initials: LJ
authors.lastname: Anstine
authors.affiliation: Department of Biomedical Engineering, Ohio State University Wexner Medical Center, Columbus, OH, USA; Davis Heart & Lung Research Institute, Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Bobba
authors.affiliation: Department of Biomedical Engineering, Ohio State University Wexner Medical Center, Columbus, OH, USA; Davis Heart & Lung Research Institute, Ohio State University Wexner Medical Center, Columbus, OH, USA; Department of Internal Medicine, Ohio State University, Columbus, OH, USA.
authors.forename: Samir
authors.initials: S
authors.lastname: Ghadiali
authors.affiliation: Center for Cardiovascular Research, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA; The Heart Center, Nationwide Children's Hospital, Columbus, OH, USA; Department of Pediatrics, Ohio State University, Columbus, OH, USA. Electronic address: joy.lincoln@nationwidechildrens.org.
authors.forename: Joy
authors.initials: J
authors.lastname: Lincoln
mesh_terms: D000375:Aging; D000818:Animals; D002450:Cell Communication; D002452:Cell Count; D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics; D016000:Cluster Analysis; D042783:Endothelial Cells / Q000378:metabolism* / Q000648:ultrastructure; D020869:Gene Expression Profiling; D006351:Heart Valves / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D059467:Transcriptome
chemical_list: D017382:Reactive Oxygen Species; D009569:Nitric Oxide
keywords: Endothelial cell; Growth; Heart valve; Maturation