Role of TGF-Beta in the Recruitment of Bone Marrow Progenitors in Vascular Injury

TGF-β 在血管损伤中骨髓祖细胞募集中的作用

• 批准号: 8002708
• 负责人: Pasithorn Suwanabol
• 金额: $ 4.39万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2011-06-23
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8002708
• 关键词: Angioplasty; Arterial Injury; Arteries; Atherosclerosis; Blood Vessels; Bone Marrow; Bone Marrow Cells; Bypass; Cell Proliferation; Complex; Development; Endarterectomy; Extracellular Matrix; Fibroblasts; Genes; Hyperplasia; Injury; Intervention; Lead; Lesion; Mediating; Molecular; Monocyte Chemoattractant Protein-1; Operative Surgical Procedures; Patients; Play; Process; Production; Proliferating; Recruitment Activity; Role; Signal Transduction; Signaling Protein; Site; Smooth Muscle Myocytes; Stem cells; Transforming Growth Factor beta; arterial remodeling; cell type; chemokine; injured; prevent; progenitor; public health relevance; restenosis; therapy development

DESCRIPTION (provided by applicant): Restenosis is a significant impediment to treatments for atherosclerosis including bypass surgery, endarterectomy, and angioplasty and stenting, and occurs in up to 30- 50% of patients following angioplasty and stenting. Understanding the molecular mechanisms that drive neointimal hyperplasia and arterial remodeling, two main contributors to restenosis, will ultimately allow for the development of therapies that prevent or halt the progression of this serious process. Restenosis is in part caused by a complex process called intimal hyperplasia. The neointimal lesion is comprised of proliferating smooth muscle cells (SMCs) and extracellular matrix. New evidence suggests that bone marrow-derived progenitor cells (BMPCs) recruited to sites of vascular injury also contribute to the neointima. BMPCs are considered multipotent in that they are capable of differentiating into numerous cell types including fibroblasts and SMCs. However, the mechanisms through which progenitor cells are recruited into the injured artery have not been described. Transforming Growth Factor-Beta (TGF-Beta), upregulated at the site of vascular injury, plays a critical role in the genesis of restenosis following vascular intervention. Our previous studies revealed that TGF-Beta's contribution to intimal hyperplasia is primarily related to cell proliferation and matrix remodeling. Moreover, TGF-Beta through its actions on SMCs may also significantly enhance progenitor cell recruitment. TGF-Beta's effect may be mediated by its signaling protein, Smad3, and lead to the production of chemokines by SMCs. Our gene array studies have demonstrated that in TGF-Beta-stimulated Smad3-expressing SMCs, Monocyte Chemotactic Protein-1 (MCP-1) is expressed over 80-fold. Our hypothesis is that TGF-Beta, through Smad3 signaling, stimulates SMCs to produce chemokines such as MCP-1, which attract bone marrow cells to the site of arterial injury thereby enhancing the development of intimal hyperplasia. PUBLIC HEALTH RELEVANCE: Restenosis is a significant impediment to treatments for atherosclerosis and occurs in up to 30-50% of patients following vascular interventions. Bone marrow-derived progenitor cells have been found to contribute to neointimal hyperplasia, one of the two main contributors to restenosis. However, the mechanisms through which progenitor cells are recruited have not been described. Our hypothesis is that TGF-Beta, through Smad3 signaling, stimulates smooth muscle cells in the vascular wall to produce factors such as monocyte chemoattractant protein-1 to attract bone marrow cells to sites of arterial injury.

描述（由申请人提供）：再狭窄是动脉粥样硬化治疗的重大障碍，包括搭桥手术，内部切除术以及血管成形术和支架，并发生在血管成形术和支架后多达30％至50％的患者中。了解驱动新内膜增生和动脉重塑的分子机制，这是再狭窄的两个主要因素，最终将允许开发预防或阻止这种严重过程发展的疗法。再狭窄部分是由称为内膜增生的复杂过程引起的。新内膜病变由增殖的平滑肌细胞（SMC）和细胞外基质组成。新的证据表明，招募到血管损伤部位的骨髓衍生的祖细胞（BMPC）也有助于新神经。 BMPC被认为是多能，因为它们能够区分多种细胞类型，包括成纤维细胞和SMC。然而，尚未描述将祖细胞募集到受伤的动脉中的机制。在血管损伤部位上调的转化生长因子β（TGF-β）在血管干预后的再狭窄起源中起着至关重要的作用。我们先前的研究表明，TGF-β对内膜增生的贡献主要与细胞增殖和基质重塑有关。此外，TGF-beta通过其对SMC的作用也可能显着增强祖细胞募集。 TGF-β的作用可能是由其信号蛋白SMAD3介导的，并导致SMC的趋化因子产生。我们的基因阵列研究表明，在TGF-beta刺激的表达SMC中，单核细胞趋化蛋白-1（MCP-1）的表达超过80倍。我们的假设是，通过SMAD3信号传导，TGF-beta刺激了SMC以产生趋化因子，例如MCP-1，这些趋化因子吸引了骨髓细胞到动脉损伤部位，从而增强了内膜增生的发展。 公共卫生相关性：再狭窄是动脉粥样硬化治疗的重大障碍，在血管干预后，多达30-50％的患者发生。已经发现骨髓来源的祖细胞有助于新内膜增生，这是再狭窄的两个主要因素之一。但是，尚未描述募集祖细胞的机制。我们的假设是，通过SMAD3信号传导TGF-beta刺激血管壁中的平滑肌细胞产生诸如单核细胞化学吸引蛋白-1的因素，以吸引骨髓细胞到动脉损伤部位。