Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, United States.
Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, United States.
J Biomech. 2021 Apr 15;119:110253. doi: 10.1016/j.jbiomech.2021.110253. Epub 2021 Feb 10.
Calcific aortic valve disease (CAVD) is a condition causing stiffening of the aortic valve, impeding cardiac function and resulting in significant morbidity worldwide. CAVD is thought to be driven by the persistent activation of the predominant cell type in the valve, aortic valve interstitial cells (AVICs), into myofibroblasts, resulting in subsequent calcification and stenosis of the valve. Although much of the research into CAVD focuses on AVICs, the aortic valve endothelial cells (AVECs) have been shown to regulate AVICs and maintain tissue homeostasis. Exposed to distinct flow patterns during the cardiac cycle, the AVECs lining either side of the valve demonstrate crucial differences which could contribute to the preferential formation of calcific nodules on the aorta-facing (fibrosa) side of the valve. Cadherin-11 (CDH11) is a cell-cell adhesion protein which has been previously associated with AVIC myofibroblast activation, nodule formation, and CAVD in mice. In this study, we investigated the role of CDH11 in AVECs and examined side-specific differences. The aorta-facing or fibrosa endothelial cells (fibAVECs) express higher levels of CDH11 than the ventricle-facing or ventricularis endothelial cells (venAVECs). This increase in expression corresponds with increased contraction of a free-floating collagen gel compared to venAVECs. Additionally, co-culture of fibAVECs with AVICs demonstrated decreased contraction compared to an AVIC + AVIC control, but increased contraction compared to the venAVECs co-culture. This aligns with the known preferential formation of calcific nodules on the fibrosa. These results together indicate a potential role for CDH11 expression by AVECs in regulating AVIC contraction and subsequent calcification.
钙化主动脉瓣疾病 (CAVD) 是一种导致主动脉瓣僵硬、阻碍心脏功能并在全球范围内导致严重发病率的疾病。CAVD 被认为是由瓣膜中主要细胞类型——主动脉瓣间质细胞 (AVIC) 持续向肌成纤维细胞转化引起的，导致随后瓣膜钙化和狭窄。尽管 CAVD 的大部分研究都集中在 AVIC 上，但主动脉瓣内皮细胞 (AVEC) 已被证明可以调节 AVIC 并维持组织内稳态。由于在心脏周期中暴露于不同的流动模式，瓣膜两侧的 AVEC 表现出关键差异，这可能导致在主动脉面（纤维层）形成优先的钙化结节。钙黏蛋白 11 (CDH11) 是一种细胞-细胞黏附蛋白，先前与 AVIC 肌成纤维细胞激活、结节形成和小鼠 CAVD 有关。在这项研究中，我们研究了 CDH11 在 AVEC 中的作用，并检查了侧特异性差异。面向主动脉的或纤维层的内皮细胞 (fibAVEC) 表达的 CDH11 水平高于面向心室的或心室的内皮细胞 (venAVEC)。这种表达的增加与游离漂浮的胶原凝胶的收缩增加相对应，与 venAVEC 相比。此外，fibAVEC 与 AVIC 的共培养显示与 AVIC+AVIC 对照相比收缩减少，但与 venAVEC 共培养相比收缩增加。这与已知的纤维层上优先形成钙化结节相一致。这些结果共同表明 AVEC 中 CDH11 的表达可能在调节 AVIC 收缩和随后的钙化中起作用。
