Flow and endothelial signaling in acquired myxomatous valve disease

项目摘要 粘液瘤性瓣膜病(MVD)发生在2-3%的人群中，原因是 二尖瓣脱垂和反流。尽管罕见的遗传性MVD形式一直是 确诊后，大多数病例发生在老年人以前健康的瓣膜中。MVD是 以瓣膜间质细胞(VIC)增殖、基质增多为特征 生产，和TGFb信号，但这些变化是如何发生在以前健康的 阀门是未知的。我们最近证明了血流动力学剪切力 流量调节KLF2和KLF4的表达直接影响心脏瓣膜发育 瓣膜内皮细胞(VECs)中的转录因子，但是否以及如何 血流动力学环境可能调节了成熟心脏瓣膜的功能 已经解决了。我们的初步研究表明，KLF2和KLF2的可诱导遗传损失 成熟血管内皮细胞中的KLF4导致与高VEC和VIC相关的MVD表型 增殖，基质沉积增加，以及病理性内皮细胞的证据- 间充质转化(EndMT)。重要的是，我们发现类似的MVD病理是 通过移植心脏的二尖瓣血流丧失引起的。这些 研究结果支持MVD的一种新机制，在这种机制中，血流动力学的变化 改变血管内皮细胞KLF2/4表达的条件可导致获得性MVD。这项建议 将使用新的基因工具测试MVD的血流动力学机制，以检查 血管内皮细胞的血流和KLF2/4控制细胞生物学(目标1)和基质生物学 (目标2)成熟的瓣膜。预计拟议的研究将提供新的见解 探讨MVD的发病机制，血流在成人心脏瓣膜稳态中的作用，以及 病理性EndMT在心血管疾病中的作用

Project Summary Myxomatous valve disease (MVD) arises in 2-3% of the human population and causes mitral valve prolapse and regurgitation. Although rare inherited forms of MVD have been identified, most cases arise in previously healthy valves in older individuals. MVD is characterized by proliferation of valve interstitial cells (VICs), increased matrix production, and TGFb signaling, but how such changes arise in previously healthy valves is unknown. We have recently demonstrated that hemodynamic shear forces direct heart valve development through expression of the flow-regulated KLF2 and KLF4 transcription factors in valve endothelial cells (VECs), but whether and how the hemodynamic environment might regulate the function of the mature heart valve has not been addressed. Our preliminary studies reveal that inducible genetic loss of KLF2 and KLF4 in mature VECs results in a MVD phenotype associated with high VEC and VIC proliferation, increased matrix deposition, and evidence of pathologic endothelial- mesenchymal transition (EndMT). Importantly, we find that similar MVD pathology is conferred by loss of blood flow across the mitral valve of transplanted hearts. These findings support a novel mechanism for MVD in which changes in hemodynamic conditions that alter VEC KLF2/4 expression give rise to acquired MVD. This proposal will test this hemodynamic mechanism for MVD using new genetic tools to examine how blood flow and KLF2/4 in VECs control the cellular biology (Aim 1) and the matrix biology (Aim 2) of the mature valve. The proposed studies are expected to provide new insight into MVD pathogenesis, the role of blood flow in adult heart valve homeostasis, and the role of pathologic EndMT in the cardiovascular disease.