The VEGFs are a family of proteins that are mitogenic for vascular endothelial cells and increase vascular permeability. VEGF is important in fetal vascular development,with VEGF levels diminishing after birth. VEGF is expressed by retinal glial cells12 and vascular endothelial cells13. VEGF is secreted by numerous ocular cell types14, and increased levels of VEGF have been detected in ocular fluids of patients with proliferative diabetic retinopathy15. In vivo, administration of neutralizing VEGF antibodies to experimental animals reverses high-glucose-induced vascular hyperpermeability16, which is an early manifestation of endothelial dysfunction in diabetic patients17.
VEGF expression is regulated largely by hypoxia, but it also accumulates in the retina early in diabetes, before any retinal hypoxia is yet apparent 18-20. It is produced by multiple cell types in the retina in diabetes, including ganglion cells, Mueller cells, and pericytes. Repeated injections of high concentrations of VEGF in the eyes of nondiabetic monkeys result in retinal changes which in some ways resemble those in the early stages of diabetic retinopathy, including vascular tortuosity and microaneurysm21, 22. Genetic factors are important in the pathogenesis of DR; there is a clear association of increased expression of VEGF with DR as well as numerous VEGF polymorphisms that are linked to increased VEGF levels and DR.23 Their result has demonstrated that the development of different stages of diabetic retinopathy is closely correlated with an increased VEGF level in the retina24.Clinical trials using anti-VEGF therapies are showing promising results against stages of diabetic retinopathy25.
VEGF is a potent vascular permeability factor, and VEGF upregulation has been linked to neovascular eye diseases including diabetic retinopathy23. VEGF-induced neovascular changes have previously been demonstrated on animal models based on increasing VEGF levels through implants26, recombinant adenovirus-mediated VEGF expression27, 28, or transgenic technologies29, 30.
In the eye, one of the earliest signs of diabetic retinopathy is retinal capillary occlusion, blocking blood flow and generating capillary-free areas31. Hypoxic conditions could develop in these capillary-free areas, and this in turn could induce the upregulation of angiogenic factor production, such as VEGF and intercellular adhesion molecules32, 33. The increased concentration of angiogenic factors would then cause vascular changes including vascular dilatations, tortuous blood vessels, microaneurysms, and endothelial cell proliferation. Subsequently,over an extended period of time, these changes could result in the development of poorly matured leaky vessels34, 35.Previous histological studies have demonstrated a strong correlation between endothelial cell proliferation, pericyte loss, and the development of microaneurysm36. Incidentally, VEGF, which is a known factor of endothelial cell proliferation, has also been shown to promote pericyte detachment and loss37.
Troglitazone and rosiglitazone, another thiazolidinediones (TZD), increase VEGF mRNA levels in 3T3-L1 adipocytes. Although increased VEGF may be beneficial for subjects with macroangiopathy and troglitazone is currently not available for clinical use, vascular complications, especially diabetic retinopathy, must be followed with great caution in subjects treated with TZD 38.
Federico et al39 tested selective PPARa and PPARy synthetic agonists potential ability to stimulate neoangiogenesis in well-established in vitro and in vivo assays. They found that specific and selective activation of PPARa and PPARy leads to increased production of VEGF, a prototypical angiogenic agent, and formation of endothelial tubules when endothelial cells are co-cultured with interstitial cells. In vivo, PPARa and PPARy synthetic agonists stimulate angiogenesis in the mouse corneal neovascularization assay, whereas fibrates and TZDs are unable to induce angiogenesis in the same experimental setting. PPARa- and PPARy-angiogenic process is associated with increased expression of VEGF and increased phosphorylation of endothelial nitric oxide (NO) synthase(eNOS) and Akt. Finally, it may be inhibited by blocking VEGF activity. The ability of PPARa and PPARy agonists to induce neoangiogenesis might have important implications for the clinical and therapeutic management of type 2 diabetes39.
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