Induction of angiogenesis by hepatocyte growth factor and nitric oxide in periodontitis

肝细胞生长因子(HGF)是从暴发性肝衰竭患者血浆中提纯的一种强有力的肝实质细胞有丝分裂原。但后来的大量研究表明，HGF具有血管生成活性等多种活性。尤其是最近的研究显示，HGF在治疗糖尿病引起的慢性阻塞性动脉硬化和足部供血不足方面具有良好的前景。顺便说一句，糖尿病患者发生牙周炎的风险更大，对牙周治疗的反应可能不如非糖尿病患者。糖尿病引起的并发症大多是由微血管阻塞引起的。在本研究中，我们重点介绍了HGF的各种活性中的血管生成活性，我们探讨了HGF在糖尿病牙周炎中的作用。首先，我们研究了ROS对HGF产生的影响，因为ROS被认为是导致各种糖尿病并发症的原因。我们发现，ROS的产生显著减少了牙龈成纤维细胞产生的HOF。这一结果表明，ROS的产生介导了作为血管生成因子的HGF的产生受到抑制。其次，我们研究了HGF和作为ROS之一的一氧化氮对血管生成的参与。此外，细胞的分支和伸长是血管形成所必需的。因此，我们研究了HGF或NO对细胞分支和延长血管形成的影响检测了信号转导抑制剂对HGF诱导的细胞分枝的影响，发现HGF和NO可相加地刺激细胞的分枝，并诱导细胞间的网络连接。此外，我们还揭示了PI3K参与了细胞的分支，而PI3K参与了基质金属蛋白的表达。这一研究表明，HGF的产生参与了糖尿病牙周炎的恶化，这是由于血管生成活性的下降所致。

Hepatocyte growth factor(HGF)is purified in plasma of patients with fulminant hepatic failure as a potent mitogen for parenchymal hepatocytes.However numerous subsequent studies have revealed that HGF has many activities such as angiogenesis activity.The recent studies, in particular, appears promising as a therapeutic agent for chronic obstructive arteriosclerosis and insufficient blood supply in the foot as a consequence of diabetes.By the way, diabetes patients are at greater risk of developing periodontitis, may not respond as well to periodontal therapy as non-diabetic patients.Almost complications due to diabetes are caused by obstruction of micro vessels.In this study we focus on the angiogenesis activity among various activities of HGF, and we examined the involvement of HGF in diabetic periodontitis.At first we examined the effects of reactive oxygen species(ROS)on HGF production because ROS such as super oxide, nitric oxide and peroxynitrite are thought to cause various diabetes complications.We revealed that ROS significantly decreased in HOF production by gingival fibroblasts.This result suggested that ROS production develop diabetes periodontitis mediated an inhibition of the production of HGF as an angiogenesis factor.Next we study the involvement of angiogenesis in HGF and nitric oxide, one of ROS.By the way, branching and elongation of cells are necessary for angiogenesis.Therefore we examined the effect of HGF or nitric oxide on branching of cells, and then we examined the effects of inhibitory agents of signal transduction on branching of cells induced by HGF.We found that HGF and nitric oxide additively stimulated branching of cells and induced cell to cell net-work. Furthermore we revealed that PI3kinase involved in the branching of cells, which involved in matrix metalloprotenases.This study shows that the involvememt of HGF production in the deteriorating of diabetic periodontitis due to decrease in an angiogenetic activity.