Molecular mechanism of proliferation of myofibroblasts in diabetic retinopathy

糖尿病视网膜病变是糖尿病最重要的血管并发症之一。众所周知，血管生成在糖尿病视网膜病变的发展中起着关键作用，但其确切机制尚不清楚。我们研究了平滑肌细胞（Sacs）去分化在动脉粥样硬化中的作用，发现Sacs的增殖是由ERK和p38MAPK级联反应的同时刺激引发的。我们还注意到动脉粥样硬化、肺纤维化、肝纤维化和肾炎有共同的发病机制。在这种情况下，平滑肌样细胞，如伊藤细胞、肺肌成纤维细胞、系膜细胞，在病变中显著增殖。我们将这种发病机制命名为“肌成纤维细胞病”，并假设糖尿病视网膜病变也包括在这个新实体中。利用分化囊的原代培养系统，我们发现不饱和溶血磷脂酸（LPA）是表型去分化最有效的诱导剂之一，在大鼠颈动脉球囊损伤模型中，给药LPA可诱导内膜增厚进展（Circulation 108:1746,2003）。我们还在条件培养基中发现了新的表型去分化诱导剂。该因子是EGF家族的成员，Epiregulin （Circulation 108:2524,2003）。表调节蛋白激活ERK和p38-MAPK级联，并迅速将Sacs的分化表型转换为去分化状态。最后，我们在糖尿病视网膜病变患者切除的组织中发现了EGF家族的过度表达和平滑肌样细胞的增殖。我们认为糖尿病视网膜病变与动脉粥样硬化有共同的发病机制。

Diabetic retinopathy is one of the most important vascular complications in diabetes. It is well known that angiogenesis plays pivotal roles in the development of diabetic retinopathy, but the precise mechanism is still unclear. We have been studied the involvement of dedifferentiation of smooth muscle cells (Sacs) in atherosclerosis and found that the proliferation of Sacs are triggered by simultaneous stimulation of ERK and p38MAPK cascades. We also noted that there are common pathogenesis in atherosclerosis, lung fibrosis, liver fibrosis, and nephritis. Under these circumstances, smooth muscle-like cells, such as Ito cells, lung myofibroblasts, mesangium cells, remarkably proliferate in the lesions. We named this pathogenesis as "Myofibroblastosis" and hypothesized that diabetic retinopathy is also included in this new entity.Using primary culture system of differentiated Sacs, we found that unsaturated lysophosphatidic acid (LPA) is one of the most potent inducer of phenotypic dedifferentiation, and administration of LPA induced progression of intimal thickening in rat carotid artery balloon-injury model (Circulation 108:1746,2003). We also identified new inducer of phenotypic dedifferentiation in the conditioned medium. This factor is a member of EGF family, Epiregulin (Circulation 108:2524,2003). Epiregulin activated both of ERK and p38-MAPK cascades and promptly exchanged the differentiated phenotype of Sacs into dedifferentiated state. Finally, we identified over-expression of EGF family and proliferation of smooth muscle-like cells in the tissue excised from the patients of diabetic retinopathy. We concluded that there is a common pathogenesis in diabetic retinopathy and atherosclerosis.