Purinergic signaling and arteriogenesis

嘌呤能信号传导和动脉生成

• 批准号: 10046293
• 负责人: Ryan M McEnaney
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-10-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10046293
• 关键词: Affect; Aging; Agonist; Anatomy; Angioplasty; Area; Arterial Occlusive Diseases; Arteries; Automobile Driving; Beds; Biochemical; Biological; Blood Vessels; Blood capillaries; Blood flow; Bypass; Caliber; Cardiovascular Diseases; Cause of Death; Cell Adhesion Molecules; Cells; Clinical; Data; Development; Diabetes Mellitus; Disease; Endothelial Cells; Endothelium; Extracellular Space; Failure; General Population; Generations; Goals; Growth; High Prevalence; Inflammation; Inflammatory; Intervention; Investigation; Ischemia; Knowledge; Laboratories; Ligation; Limb Salvage; Link; Liquid substance; Maintenance; Measures; Mechanics; Mediating; Medical; MicroRNAs; Modeling; Molecular; Nitric Oxide; Nucleotides; Operative Surgical Procedures; P2Y2 receptor; Patients; Perfusion; Pharmacology; Pharmacotherapy; Prevalence; Procedures; Process; Production; Publishing; Purinoceptor; Quality of life; Recovery; Research; Risk Factors; Role; Science; Signal Transduction; Signaling Molecule; Smoking; Stents; Stress; System; Techniques; Thick; Tissues; Translational Research; United States; Vascular Diseases; Vascular remodeling; Veins; Veterans; Vietnam; Work; agent orange; angiogenesis; arteriole; base; cost; cytokine; density; disability; extracellular; falls; femoral artery; functional status; in vivo; innovation; insight; mechanical force; military veteran; novel; novel therapeutics; prevent; receptor; receptor expression; recruit; response; shear stress; skills; success; targeted treatment; therapeutic angiogenesis; vascular bed; vascular inflammation

Arterial occlusive diseases remain responsible for the leading causes of death and disability in Western nations and have a particularly high prevalence among the Veteran population. Current therapy depends upon invasive revascularization with techniques ranging from endovascular angioplasty and stenting to open surgical vein bypass. Unfortunately, some patients are anatomically poor candidates for invasive revascularization. Arteriogenesis is the vital process of collateral artery formation, which largely occurs in areas of pre-formed arterial interconnections remote from the effects of ischemia. Arteriogenesis should not be confused with angiogenesis, a well-studied and biologically distinct mechanism through which capillary density of an ischemic tissue bed is increased. Strategies focused on “therapeutic angiogenesis” for revascularization have not been clinically successful to date. Evidence suggests that the most important factors to functional collateral development are mechanical forces - fluid shear stress and circumferential wall stress - which become increased in remote arterioles after the occlusion of a conductance artery. Unfortunately, as the vessel diameter increases, shear stress falls quickly and the impetus for growth dissipates before maximal conductance is restored. To date, the biochemical signaling mechanisms governing arteriogenesis remain largely unknown. This knowledge gap prevents development of molecular therapies that would enhance collateral growth, a conceptually important strategy for medical treatment of many vascular diseases. Nucleotides are released from cells in response to mechanical perturbations, such as increased shear stress, and function as signaling molecules. Extracellular nucleotides, acting through their receptors, activate vascular and inflammatory cells and promote their interaction, are mitogenic, and result in endothelial nitric oxide production. Our studies to date have demonstrated the P2Y2 receptor is necessary for normal collateral growth and blood flow recovery in a model of femoral artery ligation (FAL). We have also found that administration of intra-arterial nucleotides is beneficial to blood flow recovery after FAL. We therefore hypothesize that purinergic signaling governs arteriogenesis. Our hypothesis was formulated after a careful analysis of published work in the field and the generation of some key preliminary data in our own laboratory. In Aim 1, we will measure nucleotide release after FAL and identify the changes in purinergic receptor expression during collateral artery growth in order to establish a link between purinergic signaling mechanisms and collateral development. In Aim 2, we will investigate the role of purinergic signaling mechanisms in the initiation and maintenance of vascular inflammation which drives arteriogenesis. Our long term-goal is to develop a pharmacotherapy capable of enhancing collateral growth and providing a medical therapy for the effects of arterial occlusive disease. The critical insights gained through the completion of this research will enable directed pharmacological therapies for arterial occlusive disease in any vascular bed and represent a great stride toward providing medical therapy for our aging Veterans as well as the general population.

动脉闭塞性疾病仍然是西方国家死亡和残疾的主要原因。 国家，并有一个特别高的患病率在退伍军人人口。目前的治疗取决于 从血管内血管成形术和支架植入术到开放手术， 静脉搭桥不幸的是，一些患者在解剖学上是侵入性血运重建的不良候选者。 动脉生成是侧支动脉形成的重要过程，其主要发生在预形成的区域中。 远离局部缺血影响的动脉互连。动脉形成不应与 血管生成是一种经过充分研究的生物学上独特的机制，通过这种机制， 组织床增加。针对血运重建的“治疗性血管生成”的策略尚未被广泛接受。 迄今为止，临床上取得了成功。有证据表明，影响功能性侧枝循环的最重要因素 发展是机械力-流体剪切应力和周向壁应力-成为 在传导动脉闭塞后远端小动脉中增加。不幸的是，作为容器 直径增加，剪切应力福尔斯迅速下降，生长动力在最大值之前消失 电导恢复。到目前为止，控制动脉形成的生化信号机制仍然存在， 大部分未知。这种知识差距阻碍了分子疗法的发展， 侧支生长是许多血管疾病医学治疗的重要策略。 细胞在受到机械扰动（如剪切力增加）时会释放核苷酸 压力，并作为信号分子发挥作用。细胞外核苷酸，通过其受体，激活 血管和炎性细胞，并促进它们的相互作用，是促有丝分裂，并导致内皮细胞一氧化氮合酶， 氧化物生产迄今为止，我们的研究表明P2 Y2受体是正常侧支循环所必需的。 在股动脉结扎（FAL）模型中的生长和血流恢复。我们还发现 动脉内施用核苷酸有利于FAL后的血流恢复。因此我们 假设嘌呤能信号调控动脉生成。我们的假设是在 仔细分析该领域已发表的工作，并在我们自己的研究中生成一些关键的初步数据。 实验室在目标1中，我们将测量FAL后核苷酸的释放，并确定嘌呤能神经递质的变化。 受体表达，以建立嘌呤能信号传导之间的联系， 机制和抵押品开发。在目标2中，我们将研究嘌呤能信号传导的作用。 在引发和维持驱动动脉生成的血管炎症中的机制。我们漫长 长期目标是开发一种能够促进侧枝生长并提供医疗 治疗动脉闭塞性疾病的影响。通过完成这项工作获得的重要见解 研究将能够对任何血管床中的动脉闭塞性疾病进行定向药理学治疗， 代表着向为我们年迈的退伍军人和将军提供医疗服务迈出了一大步。 人口