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

描述（由申请人提供）：呼吸暂停是动脉粥样硬化治疗（包括旁路手术、动脉内膜切除术、血管成形术和支架植入术）的一个重大障碍，在血管成形术和支架植入术后，高达30- 50%的患者会发生呼吸暂停。了解驱动新生内膜增生和动脉重塑（再狭窄的两个主要贡献者）的分子机制将最终允许开发预防或阻止这一严重过程进展的治疗方法。呼吸暂停部分是由称为内膜增生的复杂过程引起的。新生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，骨髓来源的祖细胞（BMPC）招募到血管损伤部位也有助于新生内膜。BMPC被认为是多能的，因为它们能够分化成许多细胞类型，包括成纤维细胞和SMC。然而，祖细胞被募集到受损动脉中的机制尚未被描述。在血管损伤部位上调的转化生长因子-β（TGF-β）在血管介入后再狭窄的发生中起关键作用。我们以前的研究表明，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-β通过其对SMC的作用也可显著增强祖细胞募集。TGF-β的作用可能通过其信号蛋白Smad 3介导，并导致SMC产生趋化因子。我们的基因阵列研究表明，在TGF-β刺激的Smad 3表达SMC中，单核细胞趋化蛋白-1（MCP-1）表达超过80倍。我们的假设是TGF-β通过Smad 3信号传导刺激SMC产生趋化因子如MCP-1，其将骨髓细胞吸引到动脉损伤部位，从而促进内膜增生的发展。 公共卫生相关性：呼吸暂停是动脉粥样硬化治疗的一个重要障碍，在血管介入治疗后高达30-50%的患者中发生。骨髓来源的祖细胞已被发现有助于新生内膜增生，这是再狭窄的两个主要因素之一。然而，祖细胞被募集的机制尚未被描述。我们的假设是TGF-β通过Smad 3信号刺激血管壁中的平滑肌细胞产生单核细胞趋化蛋白-1等因子，将骨髓细胞吸引到动脉损伤部位。

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.