Growth and maturation of heart valves leads to changes in endothelial cell distribution, impaired function, decreased metabolism and reduced cell proliferation
Growth and maturation of heart valves leads to changes in endothelial cell distribution, impaired function, decreased metabolism and reduced cell proliferation
复制标题
DOI：
10.1016/j.yjmcc.2016.10.006
复制
发表时间：
2016-11-01
影响因子：
5
通讯作者：
Lincoln, Joy
中科院分区：
文献类型：
--
作者：
Anstine, Lindsey J.;Bobba, Chris;Lincoln, Joy
心脏瓣膜疾病的风险因素是明确的，在一生中长期暴露会导致高达33%的人口退化和功能障碍。虽然主动脉瓣置换术仍然是心血管手术中最常见的需求，尤其是在65岁以上的人群中，但进行性恶化的潜在机制尚不清楚。在其他心血管系统中，内皮细胞完整性和功能的下降在促进病理变化方面发挥了主要作用，虽然已经在瓣膜中推测了类似的机制，但缺乏支持这一点的研究。本研究的目的是研究瓣膜发育(胚胎)、生长(出生后)、维持(幼年)和衰老(老年)四个关键阶段瓣膜内皮细胞(VEC)的分布、形态、功能和转录的年龄相关变化。结合在体小鼠和体外猪的实验，我们发现血管内皮细胞的功能包括一氧化氮的生物利用度、代谢、内皮-间充质潜能、膜自我修复和增殖能力随年龄的增长而下降。此外，血管内皮细胞沿内皮细胞的分布密度降低，这与细胞形态的改变、细胞间相互作用的减少和通透性的增加有关。这些变化得到了RNA-seq分析的支持，该分析表明，与粘着、细胞周期和氧化磷酸化相关的生物学过程受到衰老的负面影响。此外，通过执行高通量分析，我们能够报告每个时间点血管内皮细胞的差异和共同转录本，这可以为揭示与年龄相关的功能障碍的机制提供见解。这些研究表明，随着时间的推移，心脏瓣膜的成熟是一个多因素的过程，本研究确定了几个可能导致瓣膜损伤的关键参数，以维持关键的结构-功能关系，导致退化和疾病。(C)2016爱思唯尔有限公司。保留所有权利。
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. (C) 2016 Elsevier Ltd. All rights reserved.