Rab27a functions in the vascular microenvironment

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Cardiovascular disease is the leading cause of death in the USA. Rates of cardiovascular disease have increased along with the prevalence of obesity. Perivascular adipose tissue (PVAT) surrounds most vessels in the body and regulates the underlying blood vessel, providing a local cellular link between obesity and cardiovascular function. In metabolically healthy individuals, PVAT induces an antiproliferative and vasorelaxation phenotype of smooth muscle cells. Conversely, in obese individuals, PVAT induces vasoconstriction. Because paracrine signaling from PVAT regulates vascular physiology, we predict that the adipocytes within PVAT are an important determinant of susceptibility to vascular disease. Our laboratory has previously shown that the trafficking molecule RAB27a is increased in mouse PVAT in a model of diet induced obesity, and also is expressed in human PVAT derived from patients with cardiovascular disease. Further, suppression of RAB27a function in human PVAT-derived preadipocytes inhibits their differentiation. This project will study the mechanism by which RAB27a controls adipogenesis in human PVAT-derived progenitors. Further, this project will determine how changes in RAB27a expression in human adipocytes changes their signaling to vascular smooth muscle cells. We hypothesize that RAB27a controls the secretion of pro- adipogenic adipokines and that these adipokines regulate both preadipocytes and potentially also vascular smooth muscle cells. To test these ideas, we have established an ongoing collection and banking of human PVAT from donors with different levels of cardiovascular disease. One group consists of patients undergoing coronary artery bypass grafting (CABG) due to severe coronary artery disease, and a second group includes patients undergoing mitral valve repair, without vascular disease. For each sample, we derive primary preadipocyte cultures from the stromal vascular fraction. Several primary preadipocyte populations from each donor type have been established. We also developed a unique three-dimensional human adiposphere model to more closely mimic the organization of PVAT in vivo. With these unique human cell models in hand, our proposal will address two aims. Aim 1 will identify the mechanism by which RAB27a regulates adipogenesis in human PVAT-derived adipocyte progenitor cells. Aim 2 will identify how RAB27a in PVAT-derived adipocytes affects paracrine secretion and smooth muscle cells. These studies will provide novel information about RAB27a function in the vascular microenvironment and how it modifies the secretion of adipokines and potential vasoactive factors. In the future, I want to be a bench researcher, and this research project is an excellent training vehicle to help me develop and improve my skills such as experimental design using human tissues, experience in translational research, and analysis of molecular and cellular characteristics compared to clinical features of donors. Through this fellowship, I will have the opportunity to develop the necessary skills to be an independent research scientist.