Maintenance and Rarefaction of the Native Collateral Circulation

原生侧支循环的维持和稀疏

• 批准号: 8876770
• 负责人: JAMES E FABER
• 金额: $ 46.8万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-26 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8876770
• 关键词: Affect; Age; Aging; Apoptosis; Arteries; Attention; Blood Circulation; Blood Vessels; Brain; Bypass; Caliber; Candidate Disease Gene; Cell Line; Cells; Cellular Structures; Chronic; Cilia; Clinical Trials; Collateral Circulation; Coronary Arteriosclerosis; Critical Pathways; Diabetes Mellitus; Disease; Disease model; Dose; Dyslipidemias; Embryo; Employee Strikes; Endothelial Cells; Environment; Environmental Risk Factor; Exercise; Exposure to; Figs - dietary; Functional disorder; Gene Expression; Gene Expression Profile; Gene Targeting; Genetic; Genetic Polymorphism; Goals; Heart; Hindlimb; Human; Hypertension; Inbred Strains Mice; Individual; Inflammatory; Injury; Intracranial Hemorrhages; Ischemia; Ligation; Limb structure; Link; Maintenance; Mediating; Metabolic syndrome; Methodology; Molecular; Molecular Profiling; Morbidity - disease rate; Mus; Obesity; Obstruction; Outcome; Patients; Peripheral; Phenocopy; Phenotype; Population; Predisposition; Preventive; Process; Research Personnel; Risk; Risk Factors; Severities; Severity of illness; Signal Pathway; Skeletal Muscle; Stroke; Structural Genes; Testing; Therapeutic; Tissues; Training; Trees; Variant; Vascular Diseases; Work; arteriole; cardiovascular risk factor; density; developmental genetics; limb injury; mortality; mouse model; neonate; novel; premature; prevent; senescence; shear stress; targeted treatment; vascular inflammation

DESCRIPTION (provided by applicant): Occlusive vascular disease of the heart, brain and peripheral limbs is the primary cause of morbidity and mortality in the US. Native (pre-existing) collaterals (COLs) interconnect adjacent arterial trees and function critically as bypass vessels i vascular obstruction occurs. Over the past 25 years investigators have focused on mechanisms mediating outward remodeling of COLs in ischemic disease. However, until our work nothing was known about what controls the number and diameter (extent) of these unique vessels in healthy tissue. We have shown that COL extent in murine brain and hindlimb varies widely due to genetic polymorphisms. Moreover, variation in extent has a greater impact on the severity of ischemic tissue injury than does variation in remodeling. Our findings have thus focused attention on the importance of under-standing the genetic mechanisms controlling extent of the native COL circulation. A major goal of the present proposal is to determine if environmental factors, ie, cardiovascular risk factors and disease (CVRFs), also adversely affect COL extent. While observations in patients suggest this could be true, our preliminary studies in mice strongly support this novel hypothesis: Aging causes an age-dose-dependent decline in COL density and diameter (rarefaction) that mechanistically links to endothelial cell/eNOS dysfunction (ECdys)-thus identifying eNOS- NO as an essential maintenance factor for COLs. In other preliminary studies we have found that COLs have remarkable structural and functional specializations, compared to arterioles in the general circulation, e.g., a flow-oriented EC alignment, abundant primary cilia (PRC), increased basal proliferation, and a unique gene expression profile. We hypothesize that this novel COL phenotype reflects the disturbed shear stress (DSS) environment in which COLs reside and is essential for their persistence. Furthermore, we postulate that this DSS environment causes accelerated proliferative EC senescence, and thus high susceptibility of COLs to premature rarefaction by CVRFs. Aim I will determine if genetic mouse models of CVRFs cause COL rarefac- tion in brain and hindlimb, leading to more severe ischemic tissue injury. AIM II will test the hypothesis that COL ECs express a unique phenotype, important for their persistence in a DSS environment and sensitivity to rarefaction by CVRFs, using in-depth cellular and molecular analyses, and conditional cell-specific gene targeting. Aim III will seek to prevent or arrest COL rarefaction in CVRF models using therapies that target EC/eNOS-dysfunction and vascular inflammation that are already in use patients or in clinical trials for other indications. Successful outcome of thes studies will define a new risk factor for ischemic disease-severity, ie, COL rarefaction, and therapeutic approaches to prevent it, and identify a novel structural/gene expression phenotype or marker that distinguishes collaterals from other vessels and which is essential for their persistence and function.

描述（由申请人提供）：心脏、大脑和周围四肢的闭塞性血管疾病是美国发病和死亡的主要原因。天然（预先存在的）侧支（COL）将相邻的动脉树相互连接，并在血管阻塞发生时在旁路血管中发挥关键作用。在过去的 25 年里，研究人员一直关注缺血性疾病中 COL 向外重塑的介导机制。然而，在我们的工作之前，我们对健康组织中这些独特血管的数量和直径（范围）的控制因素一无所知。我们已经表明，由于遗传多态性，小鼠大脑和后肢的 COL 程度差异很大。此外，程度的变化对缺血性组织损伤的严重程度的影响比重塑的变化更大。因此，我们的研究结果将注意力集中在了解控制天然 COL 循环程度的遗传机制的重要性上。本提案的主要目标是确定环境因素（即心血管危险因素和疾病 (CVRF)）是否也会对 COL 程度产生不利影响。虽然对患者的观察结果表明这可能是正确的，但我们对小鼠的初步研究有力地支持了这一新假设：衰老导致 COL 密度和直径呈年龄剂量依赖性下降（稀疏），这在机制上与内皮细胞/eNOS 功能障碍 (ECdys) 相关，从而确定 eNOS-NO 是 COL 的重要维持因子。在其他初步研究中，我们发现与大循环中的小动脉相比，COL 具有显着的结构和功能特化，例如，流向的 EC 排列、丰富的初级纤毛 (PRC)、增加的基底增殖和独特的基因表达谱。我们假设这种新的 COL 表型反映了 COL 所处的扰动剪切应力 (DSS) 环境，并且对于它们的持久性至关重要。此外，我们假设这种 DSS 环境会导致 EC 加速增殖衰老，因此 COL 对 CVRF 过早稀疏的敏感性很高。目的 我将确定 CVRF 的遗传小鼠模型是否会导致大脑和后肢 COL 稀疏，从而导致更严重的缺血性组织损伤。 AIM II 将使用深入的细胞和分子分析以及条件细胞特异性基因靶向来测试 COL EC 表达独特表型的假设，这对于它们在 DSS 环境中的持久性和对 CVRF 稀疏的敏感性非常重要。目标 III 将寻求防止或阻止 COL 稀疏化 CVRF 模型使用针对 EC/eNOS 功能障碍和血管炎症的疗法，这些疗法已在患者中使用或处于其他适应症的临床试验中。这些研究的成功结果将定义缺血性疾病严重程度的新危险因素，即 COL 稀疏，以及预防它的治疗方法，并确定一种新的结构/基因表达表型或标记，以区分络脉与其他血管，这对于络脉的持久性和功能至关重要。

项目成果

Sex Differences in the Cerebral Collateral Circulation.

• DOI: 10.1007/s12975-016-0508-0
• 发表时间: 2017-06
• 期刊: Translational stroke research
• 影响因子: 6.9
• 作者: Faber JE;Moore SM;Lucitti JL;Aghajanian A;Zhang H
• 通讯作者: Zhang H

Leptomeningeal collaterals are associated with modifiable metabolic risk factors.

• DOI: 10.1002/ana.23906
• 发表时间: 2013-08
• 期刊: ANNALS OF NEUROLOGY
• 影响因子: 11.2
• 作者: Menon, Bijoy K.;Smith, Eric E.;Coutts, Shelagh B.;Welsh, Donald G.;Faber, James E.;Goyal, Mayank;Hill, Michael D.;Demchuk, Andrew M.;Damani, Zaheed;Cho, Kyung-Hee;Chang, Hyuk-Won;Hong, Jeong-Ho;Sohn, Sung Il
• 通讯作者: Sohn, Sung Il

De-novo collateral formation following acute myocardial infarction: Dependence on CCR2⁺ bone marrow cells.

• DOI: 10.1016/j.yjmcc.2015.07.020
• 发表时间: 2015-10
• 期刊: Journal of molecular and cellular cardiology
• 影响因子: 5
• 作者: Zhang H;Faber JE
• 通讯作者: Faber JE