Differential Shear Forces on Endocardial Endothelial Cells Regulate a Fibrotic Spectrum in the Left Ventricular Outflow Tract

心内膜内皮细胞上的差异剪切力调节左心室流出道中的纤维化谱

• 批准号: 10170409
• 负责人: KATHRYN JANE GRANDE-ALLEN
• 金额: $ 52.07万
• 依托单位: RICE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10170409
• 关键词: Accounting; Address; Adult; Anatomy; Anesthesia procedures; Automobile Driving; Back; Bioreactors; Blood flow; Cardiac; Cardiopulmonary Bypass; Cardiovascular Diseases; Cell Communication; Cells; Characteristics; Child; Child Care; Clinical; Complex; Computer Models; Counseling; Cytokine Signaling; Data; Discrete Subaortic Stenosis; Disease; Endothelial Cells; Endothelium; Environment; Excision; Exposure to; Extracellular Matrix; Fibroblasts; Fibrosis; Functional disorder; Geometry; Growth; Heart; Human; Immune; Inflammation; Inflammatory; Inflammatory Response; Knowledge; Left; Lesion; Liquid substance; Mediating; Membrane; Mesenchymal; Modeling; Morbidity - disease rate; Natural History; Obstruction; Operative Surgical Procedures; Organ; Pathogenesis; Pathologic Processes; Patients; Pattern; Phenotype; Prevention; Procedures; Proteomics; Quality of life; Recurrence; Repeat Surgery; Role; Signal Transduction; Sternotomy; System; Testing; Tissues; Translating; Vascular Endothelial Cell; Ventricular; aortic valve; cellular transduction; congenital heart disorder; cost; data modeling; dynamic system; follow-up; heart function; improved; inflammatory milieu; innovation; insight; mechanical force; mechanotransduction; predictive modeling; pressure; prognostic model; response; shear stress; theories; tool

PROJECT SUMMARY Discrete subaortic stenosis (DSS) is a congenital or acquired condition that accounts for ~10% of all cases of left ventricular outflow tract (LVOT) obstruction, and is characterized by a ring of fibrous tissue below the aortic valve. Current treatment is surgical removal of the obstruction, but the unpredictable recurrence and progression of DSS leads to multiple repeat surgeries and attendant morbidity into adulthood. Current theories postulate that altered LVOT geometry causes increased shear stress and ultimately fibrosis in DSS; however, little is known about the mechanism of DSS progression. Studies in vascular endothelial cells demonstrated increased inflammation and phenotypic changes in response to altered shear forces, but effects of shear are under-studied in endocardial endothelial cells (EEC). Additionally, resident fibroblasts are implicated in organ fibrosis, including cardiac tissue, in response to altered cytokine signaling and mechanical forces. We hypothesize that that altered shear forces induce an inflammatory response by EEC, which interacts with cardiac fibroblasts (CF) to govern a fibrotic phenotype that contributes to the pathophysiology of DSS, which we will address with three specific aims. AIM 1. Elucidate the mechanisms of how shear forces regulate EEC inflammatory phenotype.First, we shall utilize patient echo data and computational modeling to develop a bioreactor that resembles altered flows in DSS. Using this innovative system, we will then test the role of CD-31 mechanosensory signaling in EEC in response to altered shear forces and geometry. Lastly, we shall investigate the effects of altered shear forces on EEC interactions with inflammatory cells in propagating a pro-inflammatory environment. AIM 2. Determine EEC transduction of altered shear forces to govern fibrosis in the LVOT. We shall investigate EEC propensity towards endoMT in response to simulated DSS altered shear and immune cell interactions. We shall then investigate the direct and inflammatory-mediated effects of EEC mechanosensing on CF that produce a fibrotic ECM. Lastly, we shall study the effect of the stiffer environment induced by fibrosis on EEC-CF crosstalk, which may propagate the fibrotic response. AIM 3. Characterize the aggressive DSS phenotype using patient data to develop a predictive model. We shall first evaluate the ECM composition, remodeling profile and echo data that characterizes the aggressive forms of DSS in humans. We shall then use these data to develop a multivariate computational model that can be used to predict an aggressive phenotype, which will be validated and tested. This proposal will improve the care of children with DSS. With completion of these aims, innovative tools and new knowledge will emerge about the effects of shear force on EEC-CF and EEC-immune cell cross-talk. These findings have potential implications for any cardiovascular disease with altered flow associated with fibrosis.

项目摘要 离散性主动脉瓣下狭窄（DSS）是一种先天性或后天性疾病，占所有 例左心室流出道（LVOT）梗阻，其特征为纤维组织环 在主动脉瓣下目前的治疗方法是手术切除梗阻，但不可预测的 DSS的复发和进展导致多次重复手术和伴随的发病率， 成年目前的理论假设，改变LVOT几何形状会导致剪切应力增加， 最终导致DSS中的纤维化;然而，关于DSS进展的机制知之甚少。研究 血管内皮细胞表现出增加的炎症和表型变化， 改变的剪切力，但在内皮细胞（EEC）中剪切的影响研究不足。 此外，常驻成纤维细胞参与器官纤维化，包括心脏组织，以响应于 改变细胞因子信号和机械力。我们假设改变的剪切力 EEC的炎症反应，其与心脏成纤维细胞（CF）相互作用以控制纤维化 表型，有助于DSS的病理生理学，我们将解决三个具体目标。 AIM 1.阐明剪切力如何调节EEC炎症表型的机制。 应利用患者回波数据和计算建模来开发类似于改变的流动的生物反应器 在DSS。使用这个创新的系统，我们将测试CD-31机械感觉信号在EEC中的作用， 对改变的剪切力和几何形状的响应。最后，我们将研究改变剪切力的影响 在传播促炎环境中与炎性细胞的EEC相互作用。 AIM 2.确定改变的剪切力的EEC转换以控制LVOT中的纤维化。我们将 研究响应于模拟DSS改变剪切和免疫的EEC对endoMT的倾向 细胞相互作用然后，我们将研究EEC的直接和炎症介导的作用 在CF上的机械感测产生纤维化ECM。最后，我们将研究更硬的 纤维化诱导的环境对EEC-CF串扰的影响，这可能传播纤维化反应。 AIM 3.使用患者数据表征侵袭性DSS表型以开发预测模型。我们 应首先评估ECM组成，重塑轮廓和回声数据，表征侵略性 人类的DSS形式。然后，我们将使用这些数据来开发一个多变量计算模型， 用于预测侵袭性表型，这将得到验证和测试。 这项建议将改善对直接资助计划儿童的照顾。随着这些目标的实现，创新 剪切力对内皮细胞-CF和内皮细胞-免疫细胞的影响将出现新的工具和知识 串话这些发现对任何血流改变的心血管疾病都有潜在的意义 与纤维化有关。

项目成果

Discrete Subaortic Stenosis: Perspective Roadmap to a Complex Disease.

• DOI: 10.3389/fcvm.2018.00122
• 发表时间: 2018
• 期刊: Frontiers in cardiovascular medicine
• 影响因子: 3.6
• 作者: Massé DD;Shar JA;Brown KN;Keswani SG;Grande-Allen KJ;Sucosky P
• 通讯作者: Sucosky P

Computational Assessment of Valvular Dysfunction in Discrete Subaortic Stenosis: A Parametric Study.

• DOI: 10.1007/s13239-020-00513-8
• 发表时间: 2021-12
• 期刊: Cardiovascular engineering and technology
• 影响因子: 1.8
• 作者: Shar JA;Keswani SG;Grande-Allen KJ;Sucosky P
• 通讯作者: Sucosky P

Congenital Heart Disease: An Immunological Perspective.

• DOI: 10.3389/fcvm.2021.701375
• 发表时间: 2021
• 期刊: Frontiers in cardiovascular medicine
• 影响因子: 3.6
• 作者: Singampalli KL;Jui E;Shani K;Ning Y;Connell JP;Birla RK;Bollyky PL;Caldarone CA;Keswani SG;Grande-Allen KJ
• 通讯作者: Grande-Allen KJ

The Immune and Inflammatory Basis of Acquired Pediatric Cardiac Disease.

• DOI: 10.3389/fcvm.2021.701224
• 发表时间: 2021
• 期刊: Frontiers in cardiovascular medicine
• 影响因子: 3.6
• 作者: Jui E;Singampalli KL;Shani K;Ning Y;Connell JP;Birla RK;Bollyky PL;Caldarone CA;Keswani SG;Grande-Allen KJ
• 通讯作者: Grande-Allen KJ

Significance of aortoseptal angle anomalies to left ventricular hemodynamics and subaortic stenosis: A numerical study.

主动脉膜角度异常对左心室血流动力学和亚电狭窄的意义：一项数值研究。

• DOI: 10.1016/j.compbiomed.2022.105613
• 发表时间: 2022-07
• 期刊: Computers in biology and medicine
• 影响因子: 7.7