Meinig School of Biomedical Engineering, Cornell University, Ithaca, United States.
Elife. 2023 Apr 20;12:e83209. doi: 10.7554/eLife.83209.
Clinically serious congenital heart valve defects arise from improper growth and remodeling of endocardial cushions into leaflets. Genetic mutations have been extensively studied but explain less than 20% of cases. Mechanical forces generated by beating hearts drive valve development, but how these forces collectively determine valve growth and remodeling remains incompletely understood. Here, we decouple the influence of those forces on valve size and shape, and study the role of YAP pathway in determining the size and shape. The low oscillatory shear stress promotes YAP nuclear translocation in valvular endothelial cells (VEC), while the high unidirectional shear stress restricts YAP in cytoplasm. The hydrostatic compressive stress activated YAP in valvular interstitial cells (VIC), whereas the tensile stress deactivated YAP. YAP activation by small molecules promoted VIC proliferation and increased valve size. Whereas YAP inhibition enhanced the expression of cell-cell adhesions in VEC and affected valve shape. Finally, left atrial ligation was performed in chick embryonic hearts to manipulate the shear and hydrostatic stress in vivo. The restricted flow in the left ventricle induced a globular and hypoplastic left atrioventricular (AV) valves with an inhibited YAP expression. By contrast, the right AV valves with sustained YAP expression grew and elongated normally. This study establishes a simple yet elegant mechanobiological system by which transduction of local stresses regulates valve growth and remodeling. This system guides leaflets to grow into proper sizes and shapes with the ventricular development, without the need of a genetically prescribed timing mechanism.
临床上严重的先天性心脏瓣膜缺陷是由于心内膜垫未能正常生长和重塑为瓣膜小叶所致。尽管已经广泛研究了基因突变，但它们只能解释不到 20%的病例。跳动的心脏产生的机械力驱动着瓣膜的发育，但这些力如何共同决定瓣膜的生长和重塑仍不完全清楚。在这里，我们将这些力对瓣膜大小和形状的影响分离开来，并研究 YAP 通路在决定瓣膜大小和形状方面的作用。低振荡剪切力促进瓣膜内皮细胞（VEC）中 YAP 的核转位，而高单向剪切力则将 YAP 限制在细胞质中。静水压力刺激瓣膜间质细胞（VIC）中的 YAP，而拉伸力则使 YAP 失活。小分子激活 YAP 可促进 VIC 增殖并增加瓣膜大小。相反，YAP 抑制增强了 VEC 中细胞-细胞黏附的表达，并影响了瓣膜形状。最后，在鸡胚心脏中进行左心房结扎以在体内操纵剪切和静水压力。左心室的限制血流导致左房室（AV）瓣呈球形且发育不全，YAP 表达受到抑制。相比之下，右 AV 瓣的 YAP 表达持续存在，正常生长和伸长。本研究建立了一个简单而优雅的机械生物学系统，通过局部应力的转导来调节瓣膜的生长和重塑。这个系统引导小叶生长成与心室发育相匹配的适当大小和形状，而无需依赖于基因规定的时间机制。
