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Skeletal Muscle and Vascular Remodeling in Peripheral Artery Disease

周围动脉疾病中的骨骼肌和血管重塑

基本信息

批准号：
9335975
负责人：
Christopher D Kontos
金额：
$ 45万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2018-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9335975
关键词：
Ablation Acute Affect Benign Blood Vessels Cell Count Cell Differentiation process Cell Proliferation Cell fusion Cell physiology Cells Cessation of life Clinical Development Differentiation Antigens Disease Endothelial Cells Event Genes Genetic Predisposition to Disease Genetic study Goals Growth Human Human Genetics In Vitro Inbred BALB C Mice Individual Injury Intermittent Claudication Ischemia KDR gene Lead Limb structure Mediating Modeling Morphology Mouse Strains Mus Muscle Muscle Cells Muscle Fibers Muscle function Natural regeneration Necrosis PECAM1 gene Patients Pattern Perfusion Peripheral arterial disease Phenotype Physiological Population Predisposition Process Receptor Signaling Recombinant adeno-associated virus (rAAV)Research Resistance Risk Role Sampling Signal Transduction Skeletal Muscle Stem cells Syndrome Testing Tissues Vascular Endothelial Growth Factor Receptor-1 Vascular Endothelial Growth Factors Vascular blood supply Vascular remodeling clinical phenotype human morbidity human mortality in vivo in vivo regeneration limb amputation mouse model muscle necrosis muscle regeneration neovascularization novel paracrine prevent public health relevance receptor response satellite cell therapeutic target vascular contributions

项目摘要

DESCRIPTION (provided by applicant): Peripheral artery disease (PAD) is a major cause of human morbidity and mortality. Evidence suggests that the most severe manifestation of PAD, critical limb ischemia (CLI), is clinically distinct from the more benign syndrome of intermittent claudication (IC). In mice, the propensity to develop CLI-like tissue necrosis is strain- dependent. Both susceptible (BALB/c) and resistant (C57BL/6) strains have been identified, suggesting that a similar genetic susceptibility exists in humans. Human genetic studies have demonstrated linkages to PAD, however the mechanisms that predispose to CLI vs. IC remain unknown. One reason for this may be that the vast majority of studies examining susceptibility to tissue necrosis in limb ischemia have focused on the vasculature. However, we have found that the skeletal muscle cell response, particularly that of skeletal muscle progenitor cells (MPCs), is a key determinant of tissue necrosis after limb ischemia in mice and susceptibility to CLI in humans. Moreover, our findings provide a novel mechanistic model that accounts for the role of known modulators of PAD, such as VEGF, in the development of CLI. In preliminary studies, we have developed a murine model of subacute limb ischemia that leads to muscle necrosis similar to that seen in humans with CLI, and we have demonstrated that: 1) in this model, but not in acute ischemia, mice develop large, mature neovessels in the non-ischemic limb; 2) these vessels contain cells that co-express the MPC marker Pax7 together with CD31, suggesting that MPCs can differentiate into endothelial cells (ECs); 3) ablation of Pax7+ MPCs results in dramatic tissue necrosis, even in necrosis-resistant mouse strains; 4) expression of the VEGF receptor VEGFR-2 on MPCs is induced by ischemia in necrosis-resistant but not necrosis-susceptible mice; 5) VEGF induces MPC proliferation and differentiation; and 6) loss of VEGFR-2 in MPCs in vivo results in deficient muscle regeneration. Taken together, these findings suggest a model in which MPCs, in response to VEGF stimulation, incorporate into new blood vessels to support tissue perfusion and protect muscle cells from ischemic injury. In addition, VEGF promotes MPCs' known direct contribution to muscle regeneration. Thus, we hypothesize that VEGF receptor signaling in endogenous muscle progenitor cells mediates both skeletal muscle neovascularization and myofiber regeneration after limb ischemia in order to limit muscle necrosis. To investigate this hypothesis, our Specific Aims are to: 1. Determine if MPC VEGF receptors are required for neovascularization and muscle regeneration in vivo. 2. Determine if paracrine VEGF signaling is required for MPC-mediated neovascularization in vivo. 3. Determine if MPC VEGF receptors are required for ischemic MPC proliferation, survival, and differentiation in vitro, and if MPCs are similarly affected in patients with CLI.