The Role of the Pericytes in the Pressure-Overloaded Heart
Abstract
Topic: The proposal relates to Cardiomyopathy, one of the FY21 PRMRP topics. We will study the role of the pericyte, a cell type that has been overlooked by myocardial biologists, in fibrotic cardiomyopathy and in heart failure. Our proposal addresses several specific areas of encouragement identified by the program, by contributing to the understanding of the pathophysiologic basis of pressure overload-induced cardiomyopathy, by dissecting molecular pathways involved in adverse remodeling and fibrotic cardiomyopathy, and by identifying therapeutic targets for treatment of patients with chronic heart failure. Background, Rationale, Hypothesis, and Specific Aims: The heart is much more than a collection of cardiomyocytes (the cardiac cells responsible for heart contraction). In addition to cardiomyocytes, the heart contains abundant vessels (comprised of endothelial cells and pericytes), fibroblasts (cells that synthesize extracellular matrix and provide structural framework for tissues), some immune cells, and a network of extracellular matrix proteins. Heart failure is associated with cardiac fibrosis, the deposition of large amounts of extracellular matrix in the interstitium and in perivascular areas. Fibrosis markedly increases the stiffness of the heart. A stiff heart fails to relax properly; as a result, pressures in the cardiac chambers increase and patients develop shortness of breath. Moreover, deposition of matrix proteins in the heart may precipitate deadly heart rhythm irregularities. Development of fibrosis involves activation of several different cell types, including macrophages, fibroblasts, and vascular cells. Pericytes are cells associated with the vascular endothelium that serve to maintain the function and integrity of the vessels. In other organs, such as the kidney and the lung, pericytes have been shown to transform into fibroblasts following injury, promoting fibrosis and dysfunction. Nothing is known regarding the role of pericytes in heart failure: these cells seem to have been forgotten by cardiac biologists. Our preliminary data identified abundant pericytes in normal and failing hearts. Moreover, using mice engineered for permanent labeling of pericytes, we obtained preliminary evidence that these cells may undergo conversion to matrix-secreting fibroblasts in a model of heart failure induced through pressure overload, thus contributing to cardiac fibrosis. Thus, our proposed studies will test the hypothesis that in the pressure-overloaded heart, pericytes respond to mechanical stimuli and growth factors, and acquire a fibrogenic phenotype that contributes to dysfunction. This hypothesis will be tested in four specific aims. Aim 1 will characterize the changes of cardiac pericytes in the failing heart and will compare their characteristics with cardiac fibroblasts. We will use newly generated reporter mice, in which pericytes and fibroblasts are labeled with a fluorescent marker. These mice will be used in order to identify fibroblasts and pericytes in pressure-overloaded hearts, to reliably harvest them, and systematically study the genes they express and their functional profiles. We will use a cutting-edge technology called single cell RNA-sequencing followed by advanced computational analysis to study the gene expression profile of each cell in order to discover new subsets of fibroblasts and pericytes in the remodeling heart. The gene expression profiles of pericytes and fibroblasts will be then related to specific functional properties. Aim 2 will study the fate of pericytes in heart failure and their contribution to cardiac fibrosis in heart failure. We will use a strategy called lineage tracing to tag pericytes prior to induction of heart failure in order to study their fate as the heart remodels. We will combine lineage tracing with single cell RNA-sequencing to study the gene expression profile of pericyte-derived cells in the failing heart, and we will characteriz
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210284
Entities
People
- Nikolaos G Frangogiannis
Organizations
- Albert Einstein College of Medicine
- United States Army