Our recent collaborative studies have determined that neurogenic stress accelerates/amplifies post-angioplasty neointima formation as well as diet-induced obesity and metabolic syndrome in rodents, by increasing the release of neuropeptide Y (NPY). NPY is a sympathetic neurotransmitter and, in some animals and humans, also a platelet-derived factor, which is potently mitogenic for vascular smooth muscle via its Y1 receptors (Rs) and angiogenic and adipogenic via its Y2Rs. The long lasting interest of the PI has been in the mechanisms of atherosclerotic lesion vulnerability and the role of bone marrow-derived progenitors (BMPs) in vascularization. While studying these processes, we developed a unique mouse model which has many features of the human vulnerable plaque. We found that chronic stress of adult apoE-/- mice increases their circulating NPY in platelets and atherosclerotic lesions, and induces marked lesion neovascularization, which is a marker for plaque vulnerability and accelerated atherosclerosis in humans. By serendipity, some of the ApoE KO mice were stressed prenatally instead of postnatally, providing intriguing preliminary data that prenatal stress alone may exert a long-term effect to promote development of atherosclerosis (and possibly metabolic syndrome), similarly to reported higher risk for cardiovascular and metabolic diseases in children born to of war- or famine-stricken populations. These initial intriguing results, together with emerging evidence that the NPY gene is highly regulated by DNA methylation and subject to stress influence (our new pilot data) have led us to develop this proposal. Its overall goal is to fully characterize this new model of prenatal stress, its impact on and mechanisms of accelerated atherosclerosis by testing the following hypothesis: Prenatal stress increases the expression of NPY and NPY receptor genes in macrophages, platelets and endothelial cells, and increases the delivery of NPY to the vessel wall, leading to augmented neointima formation, angiogenesis, inflammation, and activation of atherosclerosis in ApoE KO mice. These effects are due to stress-induced epigenetic changes in the NPY, NPY receptors and/or their signaling pathways in angiogenic and immune cell progenitors (circulating and bone-marrow derived).
This proposal seeks to understand how prenatal stress may affect the development of heart disease, specifically heart attacks, later in life. Identifying the genes and pathways through which prenatal stress impacts human disease will provide opportunities for treatment or prevention of these effects in adulthood.
