Patho-physiological studies on cellular interaction in vascular injury and vascular remodeling

血管重塑在动脉粥样硬化、血栓形成和增殖性糖尿病视网膜病变的发生和发展中的病理生理作用尚不清楚。我们对病理性血管重构的分子机制进行了研究，取得了以下结果. FGF-2决定了大鼠关节炎的严重程度因此，调控FGF-2的功能将成为类风湿关节炎的有效治疗手段. Sp1诱饵将通过同时降低癌细胞功能，包括（1）血管生成生长因子表达，（2）增殖和（3）侵袭性，有效地调节肿瘤生长。诱饵策略将成为癌症的一种选择性治疗工具。巨噬细胞浸润在野百合碱诱导的大鼠肺动脉高压模型血管重构中起重要作用。通过显性失活突变体7 ND-MCP-1调控MCP-1功能，抑制巨噬细胞浸润，为肺动脉高压的治疗提供了新的思路.通过细胞因子网络的趋生物性，新生内膜血管生成在动脉粥样硬化的进展中起重要作用.在小鼠严重肢体缺血模型中，血管生成因子（VEGF、HGF、FGF-2）在新生血管形成中具有协调的作用和层次性。此外，FGF-2基因转移对缺血肢体的坏死有保护作用，提示血管新生在血管重建中起重要作用。因此，我们将计划将我们的结果与临床应用相结合。我们现在正在向九州大学伦理委员会申请“使用SeV-FGF-2治疗严重肢体缺血患者的血管生成基因疗法的临床研究”方案。

The patho-physiological role of vascular remodeling in the development and progression of atherosclerosis, thrombosis and proliferative diabetic retinopathy, remains unclear. We studied on the molecular mechanisms of pathological vascular remodeling, and we have got the following results.1. FGF-2 determines severity of joint disease in adjuvant-induced arthritis in rats. Therefore, the control of FGF-2 function will be an effective therapeutical tool for rheumatoid arthritis.2. The Sp1 decoy would be effective for regulating tumor growth by simultaneously reducing cancer cell functions including (1) angiogenic growth factor expression, (2) proliferation, and (3) invasiveness. The decoy strategy would be an elective therapeutic tool for cancer.3. Macrophage infiltration was important for vascular remodeling in rat model of monocrotalin-induced pulmonary hypertension. The control of MCP-1 function by dominant negative mutant 7ND-MCP-1 suppressed macrophage infiltration, and thus this strategy would be provided therapeutical tool for pulmonary hypertension.4. Neointimal angiogenesis through the biotaxis by cytokine network was important for the progression of atherosclerosis.5. In a murine model of critical limb ischemia, there were harmonized effects and hierarchy of angiogenic factors (VEGF, HGF, FGF-2) in neovascularization. In addition, FGF-2 gene transfer to ischemic limbs was effective to protect limb necrosis.These findings and results suggest that angiogenesis play important roles in development of vascular remodeling. Therefore, we will plan to link our results and a clinical application successively. We are now applying, the protocol "Clinical study for angiogenic gene therapy to treat patients with critical limb ischemia using SeV-FGF-2", to Kyushu University ethical committee.