Inflammatory and Biomechanical Drivers of Endothelial-Interstitial Interactions in Calcific Aortic Valve Disease.
Inflammatory and Biomechanical Drivers of Endothelial-Interstitial Interactions in Calcific Aortic Valve Disease.
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DOI：
10.1161/circresaha.121.318011
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发表时间：
2021-04-30
影响因子：
20.1
通讯作者：
Butcher JT
中科院分区：
文献类型：
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作者：
Driscoll K;Cruz AD;Butcher JT
钙化性主动脉瓣病(CAVD)在全球范围内的负担正在急剧增加，但除了人工置换外，还没有其他治疗方法。越来越多的年轻和活跃的患者需要替代疗法。研究表明，基于生物学的诊断和治疗方法是缓解或延缓CAVD进展的机会之窗。然而，由于对推动CAVD启动和进展的复杂机制的有限了解，进展一直受到阻碍，转向临床相关的干预措施。CAVD是一种复杂的、多方面的疾病，涉及机械活动环境中瓣膜细胞的广泛炎症和转分化。早期的CAVD体外研究主要集中在瓣膜间质细胞(VIC)和瓣膜内皮细胞(VEC)的2D单一培养上。然而，这些细胞并不是孤立的，而是彼此和瓣膜中的炎性细胞协同作用，特别是在NFκB信号转导的情况下。在3D中询问多个瓣膜细胞的新实验技术已经对它们如何相互通信以及它们所处的环境产生了重要的见解。研究表明，血管内皮细胞和血管内皮细胞通过一氧化氮和细胞因子信号进行通讯，并且有很大的机会发现更多的通讯机制。虽然已知炎症细胞存在于病变的瓣膜中，但它们通过尚未阐明的机制在瓣膜疾病中发挥保护和致病作用。机械激活的实验系统已经证明，VIC和VEC对改变的机械刺激做出反应，具有类似疾病的特性。这篇综述增进了对这些关键研究领域的理解，这些研究为瓣膜特异性分子诊断学和基于生物的疗法的发展提供了希望。
Calcific aortic valve disease (CAVD) is dramatically increasing in global burden, yet no therapy exists outside of prosthetic replacement. The increasing proportion of younger and more active patients mandates alternative therapies. Studies suggest a window of opportunity for biologically based diagnostics and therapeutics to alleviate or delay CAVD progression. Advancement, however, has been hampered by limited understanding of the complex mechanisms driving CAVD initiation and progression towards clinically relevant interventions. CAVD is a complex, multifaceted disease involving widespread inflammation and transdifferentiation of resident valvular cells in a mechanically active environment. Many early in-vitro studies on CAVD focused on 2D monocultures of valvular interstitial cells (VIC) and valvular endothelial cells (VEC) cells. However, these cells do not act in isolation but rather in concert with each other and inflammatory cells in the valve, notably in the case of NFκB signaling. New experimental technologies that interrogate multiple valvular cells in 3D have yielded important insights into how they communicate with each other and their environment. Studies have demonstrated that VEC and VIC communicate using nitric oxide and cytokine signaling, and there is a large opportunity for discovery of additional communication mechanisms. Though it is known that inflammatory cells are present in diseased valves, they embody a protective and pathogenic role in valve disease through mechanisms that have yet to be elucidated. Mechanically-active experimental systems have demonstrated that VIC and VEC respond to altered mechanical stimuli with disease-like properties. This review synergizes understanding of these critical areas of research underpinning promise for the development of valve specific molecular diagnostics and biologically based therapeutics.