Flow and endothelial signaling in acquired myxomatous valve disease

项目摘要 粘液瘤性瓣膜病（MVD）在2-3%的人群中出现，并引起 二尖瓣脱垂和反流。尽管罕见的遗传性MVD已经被 大多数病例发生在老年人先前健康的瓣膜中。MVD是 特征在于瓣膜间质细胞（VIC）增殖，基质增加， 生产，和TGF β信号，但这些变化如何出现在以前的健康 阀门未知。我们最近证明了血液动力学剪切力 通过表达流量调节的KLF 2和KLF 4指导心脏瓣膜发育 转录因子在瓣膜内皮细胞（VECs），但是否以及如何 血流动力学环境可能调节成熟心脏瓣膜的功能， 已经解决了。我们的初步研究表明，KLF 2和KLF 3基因的可诱导遗传丢失可能与KLF 2基因的表达有关。 成熟VEC中的KLF 4导致与高VEC和维克相关的MVD表型 增殖，基质沉积增加，以及病理性内皮- 间充质转化（EndMT）。重要的是，我们发现类似的MVD病理学是 这是由于移植心脏二尖瓣的血流损失造成的。这些 研究结果支持了MVD的新机制，其中血流动力学的变化 改变VEC KLF 2/4表达的条件引起获得性MVD。这项建议 将使用新的遗传工具测试MVD的血流动力学机制，以研究如何 血管内皮细胞中的血流和KLF 2/4控制细胞生物学（目的1）和基质生物学 (Aim 2）成熟的瓣膜。预计拟议的研究将提供新的见解 MVD的发病机制，血流在成人心脏瓣膜稳态中的作用， 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.