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Mechanisms of PAI-1 Induced Anti-Angiogenesis

PAI-1 诱导抗血管生成的机制

基本信息

批准号：
7994173
负责人：
MARY Jo MULLIGAN-KEHOE
金额：
$ 35.98万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-04-01 至 2012-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7994173
关键词：
Address American Animals Area Arterial Fatty Streak Atherosclerosis Bathing Binding Blood Flow Velocity Blood Vessels Caliber Carotid Arteries Catheters Cause of Death Cell Surface Receptors Cholesterol Clinical Confocal Microscopy Control Animal Critiques Data Dermatitis Descending aorta Diet Disease Endothelial Cells Evaluation Family suidae Fatty acid glycerol esters Female Fibroblast Growth Factor 2 Funding Future Grant Growth Image Left Length Ligands Lipids Manuscripts Measurement Measures Medical Methodology Mus Organ PECAM1 gene Physiological Physiology Plant Roots Plasminogen Activator Inhibitor 1 Preparation Proteins Publishing Resolution Role Saline Sex Characteristics Side Signal Pathway Source Spasm Staining method Stains Sudan Surface System Testing Therapeutic Time Toxic effect Ultrasonography Vascular Diseases Vitronectin angiogenesis antiangiogenesis therapy apolipoprotein B-100 density feeding femoral artery in vivo insight male migration mouse model neovascularization novel prevent receptor research study response syndecan-4 vasa vasorum

项目摘要

DESCRIPTION (provided by applicant): Neovascularization is associated with atherosclerosis and the vasa vasorum is the primary source of angiogenic vessels that supply the neovascularized area. There is evidence that vasa vasorum density increases during plaque progression, but it remains uncertain that angiogenesis has a major role in atherosclerotic plaque growth. We have shown that a truncated plasminogen activator inhibitor-1 (PAI-1) protein, rPAI-123, has significant anti-angiogenic activity. Studies performed in this funding period show that rPAI-123 inhibits fibroblast growth factor-2 (FGF2) signaling pathways and functions. We hypothesized that rPAI-123 would inhibit angiogenic vasa vasorum in atherogenic mice to result in reduced plaque progression. The hypothesis was tested in female LDLR-/-/ ApoB-100 mice that received a high fat diet for 14 weeks prior to initiating 6 weeks of rPAI-123 (n=16) or saline (n=11) treatment with continued high fat diet. Seven control animals received normal chow diet and saline treatment. The ratio of lipid area: total area in Sudan 4 stained vessels was 60% (p< 0.001) less in the descending aorta and 30% (p<0.001) less in the aortic root of rPAI-123 treated animals when compared to high fat, saline treated mice. Reconstructed confocal microscopy images of CD31- probed vessels in the plaque area show that rPAI-123 reduced vessel area and length by 43 and 37% (p = 0.01), respectively when compared to high fat, saline treated controls. The left carotid artery circumference in high fat, rPAI-123 and high fat, saline groups were 24% (p=0.05) greater than the chow fed control. However, treatment with rPAI-123 reduced plaque area by 67% (p<0.001) and increased lumen area by 74% (p<0.001) when compared to the high fat, saline group. These data strongly support our hypothesis and additionally suggest that rPAI-123 promotes plaque regression. This proposal will further examine plaque regression in response to rPAI-123 in atherogenic female LDLR-/-/ ApoB-100 mice. Opposing effects of rPAI-123 on native PAI-1 functions will be studied in PAI-1-/-/ LDLR-/-/ ApoB-100. Finally, rPAI-123 binding interactions with potential candidate receptors will be investigated. Current medical treatment for atherosclerotic disease potentially prevents progression. A molecule that promotes plaque regression would provide profound medical advancement, thus making the proposed studies highly significant. Atherosclerosis is a prevalent vascular disease among Americans and is a leading cause of death. We have produced a truncated PAI-1 protein, rPAI-123, that has significant anti-angiogenic activity. Our preliminary results with rPAI-123 are novel, demonstrating for the first time that a modified PAI-1 protein can inhibit angiogenic vessels in a mouse model of atherosclerosis and promote plaque regression. These observations raise the possibility that rPAI-123 may ultimately have a therapeutic role in atherosclerosis. Current medical treatment for atherosclerotic disease potentially prevents progression, therefore, a molecule that promotes plaque regression would provide profound medical advancement, thus making the proposed studies highly significant.

描述（由申请人提供）：新血管形成与动脉粥样硬化相关，并且血管滋养管是供应新血管形成区域的血管生成血管的主要来源。有证据表明，血管滋养管密度在斑块进展过程中增加，但仍不确定血管生成在动脉粥样硬化斑块生长中起主要作用。我们已经证明，截短的纤溶酶原激活物抑制剂-1 (PAI-1) 蛋白 rPAI-123 具有显着的抗血管生成活性。本资助期间进行的研究表明，rPAI-123 抑制成纤维细胞生长因子 2 (FGF2) 信号通路和功能。我们假设 rPAI-123 会抑制致动脉粥样硬化小鼠的血管生成血管，从而减少斑块进展。该假设在雌性 LDLR-/-/ ApoB-100 小鼠中进行了测试，这些小鼠在开始 6 周的 rPAI-123 (n=16) 或盐水 (n=11) 治疗并持续高脂肪饮食之前接受高脂肪饮食 14 周。七只对照动物接受正常饲料和盐水治疗。与高脂肪、盐水处理的小鼠相比，rPAI-123处理的动物的降主动脉中脂质面积与总面积的比例减少了60% (p<0.001)，主动脉根部减少了30% (p<0.001)。斑块区域 CD31 探测血管的重建共聚焦显微镜图像显示，与高脂肪、盐水处理的对照相比，rPAI-123 分别减少了血管面积和长度 43% 和 37% (p = 0.01)。高脂肪、rPAI-123 和高脂肪、盐水组的左颈动脉周长比饲料喂养对照组大 24% (p=0.05)。然而，与高脂肪、盐水组相比，rPAI-123 治疗使斑块面积减少了 67% (p<0.001)，管腔面积增加了 74% (p<0.001)。这些数据有力地支持了我们的假设，并且还表明 rPAI-123 促进斑块消退。该提案将进一步检查致动脉粥样硬化雌性 LDLR-/-/ ApoB-100 小鼠中 rPAI-123 引起的斑块消退。 rPAI-123 对天然 PAI-1 功能的相反作用将在 PAI-1-/-/ LDLR-/-/ ApoB-100 中进行研究。最后，将研究 rPAI-123 与潜在候选受体的结合相互作用。目前对动脉粥样硬化疾病的治疗可能会阻止疾病的进展。促进斑块消退的分子将带来深远的医学进步，从而使拟议的研究变得非常重要。动脉粥样硬化是美国人中常见的血管疾病，也是导致死亡的主要原因。我们生产了一种截短的 PAI-1 蛋白 rPAI-123，它具有显着的抗血管生成活性。我们对 rPAI-123 的初步结果是新颖的，首次证明修饰的 PAI-1 蛋白可以抑制动脉粥样硬化小鼠模型中的血管生成，并促进斑块消退。这些观察结果提出了 rPAI-123 最终可能对动脉粥样硬化具有治疗作用的可能性。目前对动脉粥样硬化疾病的医学治疗可能会阻止疾病的进展，因此，促进斑块消退的分子将带来深远的医学进步，从而使拟议的研究具有非常重要的意义。

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）

Molecular imaging of vessels in mouse models of disease.

小鼠疾病模型中血管的分子成像。

DOI：
10.1016/j.ejrad.2009.01.053
发表时间：
2009-05
期刊：
EUROPEAN JOURNAL OF RADIOLOGY
影响因子：
3.3
作者：
Zagorchev, Lyubomir;Mulligan-Kehoe, Mary J.
通讯作者：
Mulligan-Kehoe, Mary J.

Anti-angiogenic activity of rPAI-1(23) and vasa vasorum regression.

DOI：
10.1016/j.tcm.2012.09.009
发表时间：
2013-05
期刊：
TRENDS IN CARDIOVASCULAR MEDICINE
影响因子：
9.3
作者：
Mulligan-Kehoe, Mary Jo
通讯作者：
Mulligan-Kehoe, Mary Jo

Micro computed tomography for vascular exploration.

DOI：
10.1186/2040-2384-2-7
发表时间：
2010-03-05
期刊：
Journal of angiogenesis research
影响因子：
0
作者：
Zagorchev L;Oses P;Zhuang ZW;Moodie K;Mulligan-Kehoe MJ;Simons M;Couffinhal T
通讯作者：
Couffinhal T

Advances in imaging angiogenesis and inflammation in atherosclerosis.