Mechanisms of Collateral Development and Collateral Growth in Ischemia

缺血时的侧枝发育和侧枝生长机制

• 批准号: 7655324
• 负责人: JAMES E FABER
• 金额: $ 51.42万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7655324
• 关键词: Address; Adult; Affect; Amputation; Anastomosis - action; Angiography; Arteries; Beds; Blood; Blood Circulation; Blood capillaries; Brain; Bypass; Caliber; Candidate Disease Gene; Cells; Cerebrovascular Circulation; Cessation of life; Complex; Country; Data; Development; Diffuse; Dimensions; Disease; Drops; Electroporation; Embryo; Environment; Ephrins; Face; Generations; Genes; Genetic; Genetic Polymorphism; Genomics; Growth; Heart; Hindlimb; Human; Image; In Situ; Inbred BALB C Mice; Inbred Mouse; Individual; Injury; Ischemia; Lead; Leukocytes; Limb structure; Maps; Metalcaptase; Methods; Modeling; Morbidity - disease rate; Mus; Mutant Strains Mice; Myeloid Cells; Myocardial Ischemia; Normal tissue morphology; Organ; Pattern; Perfusion; Perinatal; Peripheral; Physiological; Play; Process; Recombinants; Recovery; Reliance; Role; Signal Transduction; Site; Source; Specific qualifier value; Testing; Tissues; Trees; Variant; Vascular Diseases; Vascular Endothelial Growth Factors; Venous; Work; angiogenesis; arteriole; base; brain tissue; capillary; cell type; density; lymphatic circulation; mortality; mutant; novel; overexpression; postnatal; preconditioning; pressure; public health relevance; receptor; shear stress; therapy development

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. Angiogenesis and growth (remodeling) of collateral vessels are major adaptations that limit end-organ damage. Yet, compared to angiogenesis, much less is known about the mechanisms directing collateral growth. And no studies have determined how or when COLs develop. Collateral density and remodeling vary widely among species and humans, suggesting a genetic basis. Yet nothing is known about the source of this variation. Our preliminary studies show that COLs develop during the late embryonic-to-early postnatal period. We also find that compared to C57BL6 (B6) mice, COL formation in BALB/c (BC) mice is impaired --most dramatically in the cerebral circulation where BC essentially lack COLs. These findings create an excellent opportunity to identify factors specifying COL formation. Although multiple genes are likely involved, our preliminary work shows that BC are deficient in VEGF-A and are polymorphic at/near its locus. This, plus data from mutant mice overexpressing VEGF, suggest the novel hypothesis that VEGF signaling is crucial in COL formation. This is the first factor to be identified that regulates COL density in normal tissues. Many signals postulated to regulate COL growth in adult ischemic disease are known to be important in angiogenesis, in particular VEGF. However, VEGF's role is controversial because of difficulties in previous studies in localizing manipulation of VEGF. Also, no studies have identified the source (s) of VEGF in COL growth. To address these problems, we have developed new methods permitting 1) non-invasive imaging of COL perfusion and 2) local manipulation of VEGF signaling at the site of COL formation. Our preliminary results in the mouse hindlimb model suggest VEGF is a critical determinant of COL remodeling in ischemia. This proposal will investigate the overall hypothesis that COLs form perinatally, that VEGF signaling is central to this process, and that VEGF is also a key determinant of COL enlargement in adult ischemic disease. Aim I will determine how and when collaterals develop. Nothing is known about this fundamental process. We will also test the hypothesis that VEGF is critical in specifying collateral formation. We will characterize perinatal COL development and test the hypothesis that VEGF signaling is a key determinant and identify VEGF-R1 and -R2 involvement. Aim II will use array and genomic mapping to identify polymorphisms and VEGF-dependent and VEGF-independent candidate genes directing COL formation. Aim III will test the hypothesis that VEGF is important in collateral remodeling in adult ischemic disease, using the mouse hindlimb model, and will seek to identify the responsible mechanisms. We will use VEGF mutants, alter VEGF and its receptors, and identify the source of VEGF during COL growth. We hope our work will lead to therapies to stimulate formation of new COLs and augment growth of pre-existing COLs in occlusive vascular diseases. PUBLIC HEALTH RELEVANCE: Ischemic disease of the heart, brain and peripheral limbs, which is the most common cause of morbidity and death in western countries, is increasing worldwide, and many affected individuals are not candidates for percutaneous or bypass revascularization and are deemed "no option" (or face amputation) because of multiple vessel disease, diffuse disease or adverse preconditions. Therapies to augment angiogenesis (increase in capillary density) and arteriogenesis (enlargement of collaterals) have tremendous potential to treat ischemic disease. While several "second generation" angiogenesis trials are underway, development of therapies directed at arteriogenesis, which involves different mechanisms that are much less well understood, cannot come without a better understanding of the genetic and physiological mechanisms that specify collateral formation in normal tissue and that regulate their enlargement in ischemic disease - the specific aims of this proposal.

描述（由申请方提供）：心脏、大脑和外周肢体的闭塞性血管疾病是美国发病率和死亡率的主要原因。侧支血管的血管生成和生长（重塑）是限制终末器官损伤的主要适应。然而，与血管生成相比，对指导侧枝生长的机制知之甚少。没有研究确定COLs是如何或何时发展的。侧支密度和重塑在物种和人类之间差异很大，这表明了遗传基础。然而，我们对这种变异的来源一无所知。我们的初步研究表明，COLs的发展在胚胎晚期至出生后早期。我们还发现，与C57 BL 6（B6）小鼠相比，BALB/c（BC）小鼠的COL形成受损-在BC基本上缺乏COL的脑循环中最显着。这些发现创造了一个很好的机会，以确定具体的COL形成的因素。虽然可能涉及多个基因，但我们的初步工作表明，BC缺乏VEGF-A，并且在其位点处/附近具有多态性。这一点，加上突变小鼠过度表达VEGF的数据，表明新的假设，VEGF信号是至关重要的COL形成。这是第一个被确定的调节正常组织中COL密度的因素。许多信号被假定为在成人缺血性疾病中调节COL生长，已知在血管生成中是重要的，特别是VEGF。然而，VEGF的作用是有争议的，因为在以往的研究中，在定位操作的VEGF的困难。此外，没有研究确定COL生长中VEGF的来源。为了解决这些问题，我们已经开发了新的方法，允许1）COL灌注的非侵入性成像和2）在COL形成部位的VEGF信号传导的局部操纵。我们在小鼠后肢模型中的初步结果表明VEGF是缺血时COL重塑的关键决定因素。这项建议将调查的总体假设，COL形成围产期，VEGF信号是这个过程的核心，VEGF也是一个关键的决定因素COL扩大成人缺血性疾病。目的我将确定如何以及何时侧枝发展。我们对这个基本过程一无所知。我们还将测试的假设，VEGF是至关重要的，在指定侧支形成。我们将描述围产期COL的发展和测试的假设，VEGF信号是一个关键的决定因素，并确定VEGF-R1和-R2参与。目的II将使用阵列和基因组定位来鉴定多态性和指导COL形成的VEGF依赖性和VEGF非依赖性候选基因。目的III将使用小鼠后肢模型来检验VEGF在成人缺血性疾病侧支重塑中的重要性这一假设，并将寻求确定负责任的机制。我们将使用VEGF突变体，改变VEGF及其受体，并确定COL生长过程中VEGF的来源。我们希望我们的工作将导致治疗，以刺激新的COL的形成和增加闭塞性血管疾病中原有COL的生长。公共卫生相关性：心脏、大脑和外周肢体的缺血性疾病是西方国家发病和死亡的最常见原因，在世界范围内正在增加，许多受影响的个体不是经皮或旁路血运重建的候选者，并且由于多血管疾病、弥漫性疾病或不利的先决条件而被认为是“没有选择”（或面临截肢）。增强血管生成（毛细血管密度增加）和动脉生成（侧支扩大）的疗法在治疗缺血性疾病方面具有巨大的潜力。虽然几个“第二代”血管生成试验正在进行中，针对动脉生成的治疗方法的发展，涉及到不同的机制，这是不太好理解，不能来没有一个更好的理解的遗传和生理机制，指定在正常组织中的侧支形成和调节其扩大缺血性疾病-本提案的具体目标。