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

血管重构在动脉粥样硬化、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塑的分子机制进行了研究，取得了以下结果。在佐剂性关节炎大鼠中，成纤维细胞生长因子-2决定关节疾病的严重程度。因此，调控成纤维细胞生长因子-2的功能将成为治疗类风湿性关节炎的有效手段。Sp1诱饵通过同时降低癌细胞的功能，包括(1)血管生成生长因子的表达、(2)增殖和(3)侵袭性，从而有效地调控肿瘤的生长。诱饵策略将是癌症的一种选择性治疗工具。巨噬细胞在野百合素诱导的大鼠肺动脉高压模型血管重塑中起重要作用。显性负性突变体7ND-MCP-1对MCP-1功能的调控抑制了巨噬细胞的浸润，为治疗肺动脉高压提供了新的手段。通过细胞因子网络的生物趋化作用形成新的血管内膜对动脉粥样硬化的进展具有重要意义。在严重肢体缺血的小鼠模型中，血管生成因子(血管内皮生长因子、肝细胞生长因子、成纤维细胞生长因子-2)在新生血管形成中的作用和层次是协调的。另外，将成纤维细胞生长因子-2基因转移到缺血肢体可有效地保护肢体的坏死，提示血管生成在血管重塑的发生发展中起重要作用。因此，我们将计划将我们的结果与临床应用相继联系起来。目前，我们正在向九州大学伦理委员会申请“血管生成基因治疗严重肢体缺血的临床研究”。

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.