Flow and endothelial signaling in acquired myxomatous valve disease

获得性粘液瘤性瓣膜疾病中的血流和内皮信号传导

• 批准号: 10408810
• 负责人: MARK L KAHN
• 金额: $ 71.72万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10408810
• 关键词: ADAMTS; Address; Adult; Affect; Age; Biology; Blood flow; Canis familiaris; Cardiovascular Diseases; Cardiovascular system; Cell Proliferation; Cells; Cellular biology; Complement; DNA Sequence Alteration; Deposition; Development; Disease; Endothelial Cells; Endothelium; Environment; Event; Gene Expression; Genetic; Genetic Models; Heart Valves; Hemorrhage; Homeostasis; Human; Incidence; Individual; Inherited; Mesenchymal; Mitral Valve; Mitral Valve Prolapse; Modeling; Molecular; Mus; Pathogenesis; Pathologic; Pathology; Pathway interactions; Peptide Hydrolases; Population; Production; Proteoglycan; Proteolysis; Role; Signal Transduction; Syndrome; Testing; Tetracyclines; disease phenotype; environmental change; heart valve transplantation; hemodynamics; insight; interstitial cell; mouse genetics; mouse model; mutant; novel; paracrine; prevent; single-cell RNA sequencing; tool; transcription factor; versican

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.

项目摘要 粘液瓣疾病（MVD）出现在2-3％的人口中，原因是 二尖瓣脱垂和反流。虽然MVD的罕见形式是 确定的，大多数情况在老年人的先前健康瓣膜中产生。 MVD是 以瓣膜间质细胞（VIC）的增殖为特征，矩阵增加 生产和TGFB信号传导，但是这种变化是如何在以前健康的 阀门未知。我们最近证明了血液动力学剪切力 通过表达流动调节的KLF2和KLF4的直接心脏瓣膜发育 瓣膜内皮细胞（VEC）中的转录因子，但是否以及如何 血液动力学环境可能调节成熟心脏瓣膜的功能 已解决。我们的初步研究表明，KLF2和 成熟vec中的KLF4导致与高VEC和VIC相关的MVD表型 增殖，基质沉积增加和病理内皮的证据 间充质转变（ENDMT）。重要的是，我们发现类似的MVD病理是 由移植心脏的二尖瓣瓣膜流失的流失所赋予。这些 发现支持一种新型MVD机制，其中血液动力学变化 改变VEC KLF2/4表达的条件会引起获得的MVD。这个建议 将使用新的遗传工具测试MVD的血流动力学机制 VEC中的血流和KLF2/4控制细胞生物学（AIM 1）和基质生物学 （AIM 2）成熟阀门。预计拟议的研究将提供新的见解 进入MVD发病机理，血流在成人心脏瓣膜稳态中的作用，以及 病理EndMT在心血管疾病中的作用。