Stress and Platelet NPY in Vascular Remodeling

血管重塑中的压力和血小板 NPY

• 批准号: 7793404
• 负责人: ZOFIA ZUKOWSKA
• 金额: $ 38.72万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-08-10 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7793404
• 关键词: Acceleration; Acute; Adherence; Adhesions; Adverse effects; Agonist; Amplifiers; Androgens; Angioplasty; Animal Experimentation; Animals; Apolipoprotein E; Arterial Fatty Streak; Atherosclerosis; Blood Platelets; Blood Vessels; Cardiovascular Diseases; Cell Adhesion Molecules; Cell Communication; Cells; Chemotactic Factors; Chronic; Chronic stress; Cleaved cell; Clinical; Complex; Coronary; Data; Deposition; Development; Diabetes Mellitus; Dipeptidyl-Peptidase IV; Disease; Drug usage; Endothelial Cells; Endothelium; Enzymes; Event; Functional disorder; Glucocorticoids; Goals; Grant; Human; Hyperlipidemia; Immune; In Vitro; Inflammatory; Inflammatory Response; Injury; Intervention; Knowledge; LDL Cholesterol Lipoproteins; Lead; Lesion; Lipids; Mechanics; Mediating; Mediator of activation protein; Megakaryoblast; Megakaryocyte Proliferation; Megakaryocytes; Mitogens; Mitotic; Molecular; Mus; Nerve; Neurons; P-Selectin; Patients; Pharmaceutical Preparations; Plasma; Positioning Attribute; Process; Production; RANTES; Rattus; Research; Resistance; Risk; Risk Factors; Role; Rupture; Site; Smooth Muscle Myocytes; Staging; Stents; Stress; Stromal Cell-Derived Factor 1; Surface; System; Testing; Thick; Thrombosis; Thrombus; Time; Up-Regulation; Vascular remodeling; Xanthomas; base; cytokine; falls; high risk; in vivo; inhibitor/antagonist; injured; interest; macrophage; male; migration; monocyte; neointima formation; neuropeptide Y; novel; oxidized low density lipoprotein; prevent; receptor; response; response to injury; restenosis; uptake; vascular smooth muscle cell proliferation

DESCRIPTION (provided by applicant): Vascular remodeling in response to injury and in atherosclerosis is believed to be mediated by different mechanisms. Although platelet-monocyte-vascular cell interactions and neointima formation occur in both; inflammatory and thrombotic lesions after injury are not seen in animals. Surprisingly, we found such inflammatory atherosclerotic-like lesions post-angioplasty in rats treated perivascularly with neuropeptide Y (NPY), a sympathetic co-transmitter and vascular mitogen. While studying NPY and its receptors (Rs) in restenosis /atherosclerosis, we discovered that C57/BL mice, also used for pro- atherosclerotic ApoE-/- - do not express NPY in megakaryocytes (MK)/platelets and form mild or no lesions in response to angioplasty (neointima) and atherosclerosis (intimal xanthomas), whereas strains that do (all rats, Sv129, FVB) - develop significant lesions. Stress amplified post-angioplasty lesions and in platelet NPY-expressing rats advanced them into macrophage-rich, thrombotic atherosclerotic-like lesions. This was paralleled by a stress-induced increase in MK turnover and up-regulation of NPY expression in MK/platelets, mediated by sympathetic, NPY-ergic activation of MKs. The hypothesis that platelet NPY, at certain threshold concentrations, triggers the inflammatory cascade was formed when transfer of NPY-/- platelets into NPY+/+ mice, or Y1R antagonist completely prevented post-angioplasty macrophage transmigration and neointima formation. These intriguing data led us to propose that stress, via platelet NPY, amplifies vascular atherosclerotic remodeling by stimulating proinflammatory platelet-immune- endothelial-vascular interactions (Aim 1-3) and upregulating MK/platelet NPY expression (Aim 4). This is mediated by vascular and monocytic Y1R (Aim 1/3A), and antagonized by endothelial and macrophage-derived DPPIV/cd26 (Aim 1/3B), which inactivates NPY- Y1R-mediated and monocytic chemoattractant activities of RANTES and SDF-1 (Aim 1B). In vitro, platelet-monocyte-endothelial interactions will be studied in human and murine cells derived from mice with or without NPY, Y1R, DPPIV/cd26, or P-selectin, and in vivo, in the same mice after angioplasty with or without stress and platelet transfer (Aim 5). The critical role of monocytic Y1Rs in the platelet NPY-triggered inflammatory cascade will be tested with a conditional, monocyte-specific Y1R deletion (Y1R lox/lox crossed with Cre-Lyzs ).This will be the first time that mechanisms of actions of chronic stress on atherosclerotic remodeling will be studied at the cellular-molecular level.

描述（由申请人提供）：响应损伤和动脉粥样硬化中的血管重塑是通过不同机制介导的。尽管血小板 - 单细胞血管细胞相互作用和新内膜形成都发生在两者中。损伤后没有看到炎症性和血栓性病变。令人惊讶的是，我们发现在血管性疾病后血管成形术中的这种炎症性动脉粥样硬化样病变与神经肽Y（NPY）（一种交感神经co- co骨可以传播剂和血管促丝因）治疗。 While studying NPY and its receptors (Rs) in restenosis /atherosclerosis, we discovered that C57/BL mice, also used for pro- atherosclerotic ApoE-/- - do not express NPY in megakaryocytes (MK)/platelets and form mild or no lesions in response to angioplasty (neointima) and atherosclerosis (intimal xanthomas), whereas strains这样做（所有大鼠，SV129，FVB） - 出现重大病变。应力扩增的血管成形术后病变和表达血小板的大鼠将其引入巨噬细胞富含巨噬细胞的类似动脉粥样硬化的病变。这与MK/血小板中NPY表达的压力引起的NPY表达的上调相似，这是由MKS的交感神经，NPY-迫使激活介导的。当将NPY - / - 血小板转移到NPY+/+小鼠中，或者Y1R拮抗剂完全防止了血管成形术后巨噬细胞巨噬细胞跨移动和新症形成时，在某些阈值浓度下的血小板NPY触发了炎症级联反应的假说。这些有趣的数据使我们提出，通过血小板NPY进行压力，通过刺激促炎血小板 - 免疫 - 免疫 - 内皮血管相互作用（AIM 1-3）和上调MK/Platlet NPY NPY表达（AIM 4）来扩增血管性动脉粥样硬化重塑。这是由血管和单核细胞Y1R（AIM 1/3A）介导的，并由内皮和巨噬细胞衍生的DPPIV/CD26（AIM 1/3B）拮抗，这使NPY-Y1R介导的npy-y1R介导的和单核细胞化学的化学剂活性和单核化性化剂活性（Rantes and Sdf-1）（AIM 1B）（AIM 1B）。在体外，血小板 - 单位细胞 - 内皮相互作用将在具有或不具有NPY，Y1R，DPPIV/DPPIV/CD26或p-链霉素的小鼠的人和鼠细胞中进行研究，并在体内，在血管成形术后具有或无压力和血小板转移的同一小鼠中（AIM 5）。单核细胞Y1R在血小板NPY触发的炎症性级联反应中的关键作用将通过条件，单核细胞特异性的Y1R缺失（Y1R LOX/LOX与CRE-Lyzs交叉）。这将是第一次对年要压力对逐步进行的重新调整的机制。