Vascular smooth muscle cell heterogeneity and disease

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Project Summary Vascular cell heterogeneity is a fascinating but poorly understood phenomenon. Numerous vascular cell types undergo fate transitions under pathological conditions. This includes endothelial cells (ECs) undergoing endothelial-to-mesenchymal transition (EndMT) and acquiring certain characteristics typical of macrophages and smooth muscle cells (SMCs). SMCs, in turn, can also acquire macrophage-like features while bone marrow-derived mononuclear cells can express certain EC and SMC markers when present at sites of chronic inflammation. These cells fate transitions have been linked to various pathologies including atherosclerosis, aneurysms, pulmonary hypertension and cavernous cerebral malformations. While the existence of these cell fate transitions is now well accepted, little is known about the origin and characteristics of SMCs undergoing these fate changes. Our preliminary data suggest that certain subpopulations of normal SMCs are particularly prone to phenotypic modulation and are predominately pathogenic. We hypothesize that a small subpopulation of normal SMCs is responsible for pathogenesis of CV diseases associated with expansion of the SMC pool and that targeting these cells might prove to be a better and more specific therapeutic approach. It is our goal in this application to define these cell populations, determine what drives their pathogenic responses and begin identifying therapeutic approaches to controlling CV illnesses driven by specifically targeting these SMC subsets.