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

该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。我们主要集中在血管生成和血管通透性因子，如血管内皮生长因子和血管生成素(Ang1，2)的分子机制。肾素-血管紧张素系统已被证明在视网膜病变的发生发展中起关键作用。我们的研究结果表明，ALL通过增加视网膜微血管周细胞分泌血管内皮生长因子和血管内皮细胞VEGFR2和Ang2来刺激血管异常。此外，ALL诱导的反应是通过AT1受体、PKC依赖的信号和AP1介导的转录调节来介导的。这些分子可能成为抑制视网膜病变早期事件的靶点。血管紧张素转换酶2也被证明会恶化内皮细胞与内皮细胞周围的相互作用。我们的研究表明，在体外或体内模型中，血管内皮生长因子、缺氧和糖尿病选择性地上调了Ang2的表达。这些发现可能提示该分子的上调可能是周细胞丢失的机制之一，周细胞丢失是一种重要的病理变化，被证明是促进血管增生性和血管通透性异常的触发因素。由于短期糖尿病动物视网膜中的白细胞行为与血管通透性反应有关，我们研究了一种机制，发现PKCβ特异性抑制白细胞的捕获和侵袭。综上所述，抑制血管内皮生长因子的调节机制和周细胞变性如ALL、Ang2和相关的信号系统可能是阻止视网膜病变早期病理事件的关键靶点。

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