Elucidation of the regulatory mechanism for vascular endothelial growth factor (VEGF) expression in diabetic retinopathy

阐明糖尿病视网膜病变中血管内皮生长因子（VEGF）表达的调节机制

• 批准号: 11694267
• 负责人: HONDA Yoshihito
• 金额: $ 5.5万
• 依托单位: KYOTO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A).
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11694267/
• 关键词: Diabetic Retinopathy; neevascularization; Angiopoietin; Angiotensin; pericyte; endothelium; VEGF; ischemia; 血管内皮増殖因子; アンジオテンシン; Tie2; 低酸素

The aim of the study is to elucidate the mechnaism of pathogenesis in early stages of diabetic retinopathy and to develop new strategies to halt the initiation of retinopathy. We mainly focused on the molecular mechanism associated with angiogenic and vasopermeable factors such as vascular endothelial growth factor (VEGF) and angiopoietins (Ang1, 2). Renin-angiotensin system has been shown to be a key player in the development of retinopathy. Our findings demonstrated that All stimulates the vascular abnormalities by increasing VEGF secretion in pericytes and VEGFR2 and Ang2 expression in endothelial cells in retinal microvasculature. In addition, the All-induced response is mediated through AT1 receptor, PKC dependent signaling, and AP1-mediated transcriptional regulation. These molecules could be targets to suppress early events of retinopathy. Ang2 has also been shown to deteriorate endo-periendothelial interaction. Our study revealed that Ang2 is seletively upregulated by VEGF, hypoxia, and diabetes mellitus in vitro or in vivo model. These findings might suggest that the upregulation of the molecule could be one of mechanisms on pericyte loss, which is a significant pathological change as shown to be a trigger to promote vasoproliferative and vasopermeable abnormalities. Since the leukocyte behavior is associated with vasopermeable response in the retina of short-term diabetic animal, we investigated a mechanism and found that PKCβ specific inhibition suppressed leukocyte trapping and invasion. Taken together, inhibition of regulatory mechnism of VEGF and pericyte degeneration such as All, Ang2, and the related-signaling system could be key targets to halt early pathological events of retinopathy

本研究的目的是阐明糖尿病视网膜病变早期的发病机制，并开发新的策略来阻止视网膜病变的发生。我们主要集中在与血管生成和血管通透性因子，如血管内皮生长因子（VEGF）和血管生成素（Ang 1，2）的分子机制。肾素-血管紧张素系统已被证明是视网膜病变发展的关键因素。我们的研究结果表明，All通过增加周细胞中VEGF的分泌以及视网膜微血管中内皮细胞中VEGFR 2和Ang 2的表达来刺激血管异常。此外，All诱导的应答通过AT 1受体、PKC依赖性信号传导和AP 1介导的转录调节介导。这些分子可能是抑制视网膜病变早期事件的靶点。Ang 2也被证明会恶化内皮-内皮周围的相互作用。我们的研究表明，血管生成素2是选择性上调VEGF，缺氧，糖尿病在体外或体内模型。这些发现可能表明该分子的上调可能是周细胞损失的机制之一，周细胞损失是一种重要的病理变化，如显示为促进血管增殖和血管通透性异常的触发因素。由于白细胞的行为与短期糖尿病动物视网膜的血管通透性反应有关，我们研究了一种机制，发现PKCβ特异性抑制抑制白细胞的捕获和侵袭。总之，抑制VEGF和周细胞变性的调节机制，如A1、Ang 2和相关信号系统，可能是阻止视网膜病变早期病理事件的关键目标

项目成果

高木均: "虚血後の血管新生はどのようにして起こるのか"細胞工学特集「虚血分子メカニズムと新しい治療法」. 6 (2000)

Hitoshi Takagi：“缺血后血管生成如何发生？”细胞工程专题“缺血的分子机制和新的治疗方法”6（2000）。

Otani A: "Angiotensin II-stimulated vascular endothelial growth factor expression in bovine retinal pericytes."Invest Ophthalmol Vis Sci.. 41. 1192-9 (2000)

Otani A：“牛视网膜周细胞中血管紧张素 II 刺激的血管内皮生长因子表达。”Invest Ophasemol Vis Sci.. 41. 1192-9 (2000)

Suzuma K: "Increased expression of KDR/Flk-1 (VEGFR-2) in murine model of ischemia-induced retinal neovascularization."Microvasc Res.. 56. 183-91 (1998)

Suzuma K：“缺血诱导的视网膜新生血管小鼠模型中 KDR/Flk-1 (VEGFR-2) 的表达增加。”Microvasc Res.. 56. 183-91 (1998)

大谷篤史: "Expressions of angiopoietins and Tie 2 in human choroidal neovascular membranes"Invest Ophthalmol Vis Sci. 40. 1912-1920 (1999)

Atsushi Otani：“人脉络膜新生血管膜中血管生成素和 Tie 2 的表达”Invest Ophasemol Vis Sci 40。1912-1920 (1999)

Otani A. 他: "Angiotensin stimulates vascular endothelial growth factor expression in Dovine retinal microvascular cells"Invest Ophthalmol Vis Sci. (in press).

Otani A. 等人：“血管紧张素刺激Dovine 视网膜微血管细胞中血管内皮生长因子的表达”Invest Ophasemol Vis Sci（出版中）。