# Diabetic Retinopathy and Ocular Melanoma: How Far We Are?
## 3 Diabetic Retinopathy, Angiogenesis and Anti-Angiogenic Therapy
All of this knowledge has led to the conclusion that diabetes-related retinal dysfunction is a retinal neurovascular change, highlighting the association between retinal neurons (photoreceptors, horizontal and bipolar cells, amacrine and ganglion cells), support cells (astrocytes and Muller glial cells) and vascular beds (endothelial cells and pericytes). Thus, the performance of this retinal neurovascular unit is crucial for its normal functioning, allowing its adaptation to the most diverse physiological conditions [5]. As mentioned before, DR results in microvascular changes and a failure in BRB function, succeeding the development of macular edema [70; 71]. Thus, over time there has been an attempt to study and explain these mechanisms. Several pathways describing the molecular mechanisms of DR are now known, including the polyol pathway, advanced glycated-end products, protein kinase C pathway, oxidative stress, renin-angiotensin system and epigenetics, as well as VEGF [3]. Inflammation plays a crucial role in DR. The high blood glucose levels typical in diabetes activate the secondary pathway for glucose metabolism--the polyol pathway. In turn, aldose reductase reduces glucose in sorbitol, while sorbitol dehydrogenase metabolizes sorbitol in fructose. Accumulation of sorbitol inside the cells leads to osmotic changes in retinal vascular cells and in RPE cells, loss of pericytes, change in basement membrane size and oxidative stress. The activation of this pathway further promotes the breakdown of BRB that occurs in DR [72]. The resulting glycated products correspond to proteins and lipids that at the end of translation are exposed to aldose sugars, being transformed by non-enzymatic glycation and oxidation [73]. These resulting products are related to DR, as they change hormones, cytokines and extracellular matrix and further induce retinal vascular damage [74; 75]. The generation of reactive oxygen species (ROS), which results from the excess of sugar in the blood, stimulates oxidative stress, which is responsible for the activation of other mechanisms promoting DR [76; 71]. In this disease, the renin-angiotensin system also has a crucial role as it also leads to damage to neuronal vascular cells and retina [77]. Diabetes induces epigenetic changes (DNA methylation, histone acetylation and post-transcriptional RNA regulation) that lead to altered gene expression (genes involved in oxidation, angiogenesis, extracellular matrix degradation), which modifies the function of retinal vascular cells that are crucial in DR [78; 79]. Through the analysis of in vitro and in vivo studies, several characteristics of inflammation have been detailed, such as leukostasis, neutrophil and macrophage infiltration, complement and microglial induction, positive regulation of cytokines, as well as blood flow expansion, vascular permeability and tissue edema [3]. To counter the macular edema and BRB rupture that occur in DR, steroids are usually recommended [80; 81]. Regarding growth factors, these (especially VEGF-A) enhance the action of retinal ICAM-1, vascular permeability, leukostasis and BRB breakdown [82]. For the treatment of DR, anti-VEGF drugs have been commonly used, but these require several injections and are associated to limited efficacy [83]. In a rat model study, induced hyperglycaemia increased expression of VEGF, which was mediated through the protein kinase C\(\beta\)/human antigen R (HuR) and phospholipase A2 pathways [84; 85]. siRNA-containing lipid nanocarriers have also been studied, proving to be an alternative to DR therapy. These nanocarriers inhibit HuR and phospholipase A2, not allowing increased retinal VEGF levels [85; 86]. Excess of glucose interferes with plasma tumour necrosis alpha (TNF\(\alpha\)) and interleukin 6 (IL6) and VEGF plasma levels, and reduced retinal oxygen levels stimulate the release of macrophages, chemokines and microglial growth factors, as well as the expression of angiogenic factors [87; 88; 89; 90].