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Mechanisms of Collateral Development and Collateral Growth in Ischemia

缺血时的侧枝发育和侧枝生长机制

基本信息

批准号：
8130993
负责人：
JAMES E FABER
金额：
$ 51.38万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-01 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8130993
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 Collateral Circulation Complex Country Data Development Diffuse Dimensions Disease Drops Electroporation Embryo Environment Ephrins Face Generations Genes Genetic Genetic Polymorphism Genomics Growth Health 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 receptor shear stress therapy development

项目摘要

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(申请人提供)：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。血管生成和侧支血管的生长(重塑)是限制终末器官损害的主要适应。然而，与血管生成相比，人们对侧枝生长的指导机制知之甚少。也没有研究确定COL是如何或何时发展起来的。侧支密度和重塑在物种和人类之间差异很大，表明存在遗传基础。然而，人们对这种变异的来源一无所知。我们的初步研究表明，COL在胚胎晚期到出生后早期发育。我们还发现，与C57BL6(B6)小鼠相比，BALB/c(BC)小鼠的Col形成受到损害--最显著的是在BC基本上缺乏COL的脑循环中。这些发现创造了一个绝佳的机会来确定指定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缺乏血管内皮生长因子-A，并且在其基因座/附近具有多态性。这一点，加上过度表达血管内皮生长因子的突变小鼠的数据，表明了一种新的假设，即血管内皮生长因子信号在COL的形成中起关键作用。这是第一个被确定的调节正常组织中Col密度的因素。许多信号被认为在成人缺血性疾病中调节COL的生长在血管生成中很重要，尤其是血管内皮生长因子。然而，由于先前的研究在定位血管内皮生长因子的操作上存在困难，血管内皮生长因子的作用是有争议的。此外，还没有研究确定血管内皮生长因子在COL生长中的来源(S)。为了解决这些问题，我们开发了新的方法，允许1)Col灌注的非侵入性成像和2)在Col形成部位局部操作VEGF信号。我们在小鼠后肢模型上的初步结果表明，血管内皮生长因子是缺血时COL重塑的关键决定因素。这项建议将调查COL在围产期形成的总体假设，即血管内皮生长因子信号在这一过程中是核心的，以及血管内皮生长因子也是成人缺血性疾病中COL增大的关键决定因素。目的我将确定侧脉如何以及何时发展。人们对这一基本过程一无所知。我们还将检验这一假设，即血管内皮生长因子在确定侧枝形成方面起着关键作用。我们将描述围产期COL的发育特征，并验证VEGF信号是一个关键决定因素的假设，并确定VEGF-R1和-R2的参与程度。目的II将使用阵列和基因组图谱来确定多态和指导COL形成的依赖和不依赖于VEGF的候选基因。目的III将利用小鼠后肢模型验证血管内皮生长因子在成人缺血性疾病侧支重塑中的重要作用这一假说，并试图确定其相关机制。我们将利用血管内皮生长因子突变体，改变血管内皮生长因子及其受体，并确定血管内皮生长因子的来源。我们希望我们的工作将导致治疗，以刺激新的COLS的形成，并增加先前存在的COLS在闭塞性血管疾病中的生长。公共卫生相关性：心、脑和外周肢体的缺血性疾病是西方国家最常见的发病和死亡原因，在全球范围内正在增加，许多受影响的人不适合接受经皮或旁路血管重建术，并因多支血管疾病、弥漫性疾病或不利的先决条件而被视为“没有选择”(或面部截肢)。促进血管生成(毛细血管密度增加)和动脉生成(侧支扩大)的治疗方法在治疗缺血性疾病方面具有巨大的潜力。虽然几项“第二代”血管生成试验正在进行中，但针对动脉生成的治疗方法的开发，涉及到不同的机制，而这些机制知之甚少，如果不能更好地理解遗传和生理机制，这些机制指定了正常组织中侧支的形成，并调节它们在缺血性疾病中的扩大--这是这项提议的具体目标。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Genetic variation in retinal vascular patterning predicts variation in pial collateral extent and stroke severity.

视网膜血管模式的遗传变异可预测软脑膜侧支范围和中风严重程度的变化。

DOI：
10.1007/s10456-014-9449-y
发表时间：
2015
期刊：
Angiogenesis
影响因子：
9.8
作者：
Prabhakar,Pranay;Zhang,Hua;Chen,De;Faber,JamesE
通讯作者：
Faber,JamesE

Aging-induced collateral dysfunction: impaired responsiveness of collaterals and susceptibility to apoptosis via dysfunctional eNOS signaling.

DOI：
10.1007/s12265-011-9280-4
发表时间：
2011-12
期刊：
JOURNAL OF CARDIOVASCULAR TRANSLATIONAL RESEARCH
影响因子：
3.4
作者：
Wang, Jinsong;Peng, XinZhi;Lassance-Soares, Roberta M.;Najafi, Amir H.;Alderman, Lee O.;Sood, Subeena;Xue, Zhenyi;Chan, Rosanna;Faber, James E.;Epstein, Stephen E.;Burnett, Mary Susan
通讯作者：
Burnett, Mary Susan

Formation of the collateral circulation is regulated by vascular endothelial growth factor-A and a disintegrin and metalloprotease family members 10 and 17.