Calcific aortic valve disease (CAVD) is a common cardiovascular disease that affects millions of people worldwide. The disease is characterized by the formation of calcium nodules on the aortic valve leaflets, which can lead to stenosis and heart failure if left untreated. The pathogenesis of CAVD is still not well understood, but involves several signaling pathways, including the transforming growth factor beta (TGF\(\beta\)) pathway. In this study, we developed a multiscale computational model for TGF\(\beta\)-stimulated CAVD. The model framework comprises cellular behavior dynamics, subcellular signaling pathways, and tissue-level diffusion fields of pertinent chemical species, where information is shared among different scales. Processes such as endothelial to mesenchymal transition (EndMT), fibrosis, and calcification are incorporated. The results indicate that the majority of myofibroblasts and osteoblast-like cells ultimately die due to lack of nutrients as they become trapped in areas with higher levels of fibrosis or calcification, and they subsequently act as sources for calcium nodules, which contribute to a polydispersed nodule size distribution. Additionally, fibrosis and calcification processes occur more frequently in regions closer to the endothelial layer where the cell activity is higher. Our results provide insights into the mechanisms of CAVD and TGF\(\beta\) signaling and could aid in the development of novel therapeutic approaches for CAVD and other related diseases such as cancer. More broadly, this type of modeling framework can pave the way for unraveling the complexity of biological systems by incorporating several signaling pathways in subcellular models to simulate tissue remodeling in diseases involving cellular mechanobiology.

钙化性主动脉瓣疾病（CAVD）是一种常见的心血管疾病，影响全世界数百万人。该疾病的特点是主动脉瓣叶上形成钙结节，如果不及时治疗，可能会导致狭窄和心力衰竭。 CAVD 的发病机制尚不清楚，但涉及多种信号通路，包括转化生长因子β (TGF\(\beta\)) 通路。在这项研究中，我们开发了 TGF\(\beta\) 刺激的 CAVD 的多尺度计算模型。该模型框架包括细胞行为动力学、亚细胞信号通路和相关化学物质的组织水平扩散场，其中信息在不同尺度之间共享。内皮向间质转化 (EndMT)、纤维化和钙化等过程都被纳入其中。结果表明，大多数肌成纤维细胞和成骨细胞样细胞最终因缺乏营养而死亡，因为它们被困在纤维化或钙化程度较高的区域，随后它们成为钙结节的来源，从而导致多分散结节尺寸分布。此外，纤维化和钙化过程更频繁地发生在靠近内皮层的区域，那里的细胞活性较高。我们的研究结果提供了对 CAVD 和 TGF\(\beta\) 信号传导机制的深入了解，并有助于开发 CAVD 和其他相关疾病（如癌症）的新治疗方法。更广泛地说，这种类型的建模框架可以通过在亚细胞模型中整合多种信号通路来模拟涉及细胞力学生物学的疾病中的组织重塑，从而为揭示生物系统的复杂性铺平道路。