Prenatal stress and accelerated atherosclerosis in ApoE knockout mice

描述（由申请人提供）：我们最近的合作研究已经确定，神经源性应激通过增加神经肽Y（NPY）的释放，加速/放大了啮齿动物血管成形术后新生内膜形成以及饮食诱导的肥胖和代谢综合征。NPY是一种交感神经递质，在一些动物和人类中，也是一种血小板衍生因子，其通过其Y1受体（Rs）有效地促进血管平滑肌的有丝分裂，并通过其Y2 Rs促进血管生成和脂肪生成。PI长期关注动脉粥样硬化病变易损性的机制和骨髓源性祖细胞（BMPs）在血管形成中的作用。在研究这些过程的同时，我们开发了一种独特的小鼠模型，该模型具有人类易损斑块的许多特征。我们发现成年apoE-/-小鼠的慢性应激增加了血小板和动脉粥样硬化病变中的循环NPY，并诱导了明显的病变新血管形成，这是人类斑块脆弱性和加速动脉粥样硬化的标志。通过偶然的发现，一些ApoE基因敲除小鼠在产前而不是产后受到压力，提供了有趣的初步数据，产前压力本身可能会产生长期影响，促进动脉粥样硬化（可能是代谢综合征）的发展，类似于报道的战争或饥荒人口出生的儿童患心血管和代谢疾病的风险较高。这些最初有趣的结果，以及新出现的证据表明，NPY基因受到DNA甲基化的高度调节，并受到压力的影响（我们的新试点数据），使我们提出了这一建议。其总体目标是通过检验以下假设，充分描述产前应激的新模型及其对加速动脉粥样硬化的影响和机制：产前应激增加了巨噬细胞、血小板和内皮细胞中NPY和NPY受体基因的表达，并增加了NPY向血管壁的递送，导致新生内膜形成、血管生成、炎症，以及ApoE KO小鼠中动脉粥样硬化的活化。这些效应是由于在血管生成和免疫祖细胞（循环和骨髓来源）中的NPY、NPY受体和/或其信号传导途径中的应激诱导的表观遗传变化。 公共卫生相关性：这项提案旨在了解产前压力如何影响心脏病的发展，特别是心脏病发作，在以后的生活中。确定产前压力影响人类疾病的基因和途径将为治疗或预防成年后的这些影响提供机会。

DESCRIPTION (provided by applicant): 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). PUBLIC HEALTH RELEVANCE: 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.