Prenatal stress and accelerated atherosclerosis in ApoE knockout mice

描述(申请人提供)：我们最近的合作研究已经确定，神经性应激通过增加神经肽Y(NPY)的释放，加速/放大啮齿动物血管成形术后新生内膜的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，在某些动物和人类中也是一种血小板衍生因子，它通过其Y1受体(Rs)促进血管平滑肌有丝分裂，并通过其Y2Rs促进血管生成和脂肪生成。PI对动脉粥样硬化病变易损性的机制和骨髓来源的祖细胞(BMP)在血管形成中的作用一直是人们长期关注的问题。在研究这些过程时，我们开发了一种独特的小鼠模型，它具有人类脆弱斑块的许多特征。我们发现，成年apoE-/-小鼠的慢性应激增加了其在血小板和动脉粥样硬化病变中的循环NPY，并诱导了显著的病变新生血管，这是人类斑块易损性和加速动脉粥样硬化的标志。巧合的是，一些ApoE KO小鼠在出生前而不是出生后受到应激，提供了有趣的初步数据，即仅产前应激就可能对促进动脉粥样硬化(可能还有代谢综合征)的发展产生长期影响，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性疾病的风险更高。这些最初耐人寻味的结果，以及新出现的证据表明，NPY基因受到DNA甲基化的高度调控，并受到压力的影响(我们的新的试点数据)，促使我们制定了这一建议。它的总体目标是通过检验以下假设来全面描述这一新的产前应激模型及其对动脉粥样硬化加速的影响和机制：产前应激增加巨噬细胞、血小板和内皮细胞中NPY和NPY受体基因的表达，并增加NPY向血管壁的输送，导致ApoE KO小鼠新的内膜形成、血管生成、炎症和动脉粥样硬化的激活。这些效应是由于应激诱导血管生成和免疫细胞前体(循环和骨髓来源)的NPY、NPY受体和/或它们的信号通路的表观遗传变化。 公共卫生相关性：这项建议试图了解产前应激可能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。确定产前应激影响人类疾病的基因和途径将为成年后治疗或预防这些影响提供机会。

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.