Diabetic Retinopathy Pathophysiology
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Diabetic retinopathy (DR) is the most common microvascular complication in diabetic patients and the leading global cause of vision loss in working middle-aged adults.  It can be classified clinically into non-proliferative (NPDR) and proliferative (PDR) forms, according to the presence or absence of retinal neovascularization, and it can present with or without macular edema (DME).
NPDR represents the early stage of DR, with increased vascular permeability and capillary occlusion being the two main observations in retinal vasculature. Based on the severity of retinal vascular lesions, NPDR is categorized into mild, moderate, and severe forms. Lesions vary from microaneurysms, dot and blot hemorrhages, hard exudates, and cotton wool spots to venous beading and intra-retinal microvascular abnormalities (IRMAs).  PDR represents a more advanced stage of DR, being characterized by the presence of neovascularization. The new abnormal vessels may bleed into the vitreous or cause a tractional retinal detachment, severely impairing vision. DME is characterized by thickening of the macula due to the accumulation of fluid within 500 µm of the center of the macula and it can occur at any stage of DR  In patients with type I diabetes, PDR is the most prevalent vision-threatening condition. However, the most common cause of vision loss in type II diabetes patients is DME.
For patients with mild to moderate NPDR, it is crucial to achieve systemic control of hyperglycemia, hypertension, and dyslipidemia in order to prevent the progression and even to reverse the severity of retinopathy. For severe NPDR, if a frequent follow-up is not guaranteed (<3 months) panretinal photocoagulation (PRP) is used to ablate ischemic areas of retina, reducing pro-angiogenic stimulus.  For PDR, PRP should be applied immediately outside of the macular area. In recent studies, it has been shown that anti-VEGF injections for DME seem to suppress the progression to PDR, lessen the severity of PDR and even result in better visual acuity and lower rates of vitreous hemorrhage, retinal detachment, and neovascular glaucoma when compared with PRP in patients with PDR. Even though these reports seem very promising, given the chronic nature of PDR and the intravitreal half-life of anti-VEGF drugs currently in use, the main disadvantage of anti-VEGF monotherapy for PDR is that these drugs need to be administered periodically. Interruption of treatment can be catastrophic and lead to irreversible blindness. In case of vitreous hemorrhage or tractional retinal detachment, vitrectomy should be performed.
DME was first treated with focal lasers for leaky microaneurysms and grid lasers for areas of diffuse leakage and capillary non-perfusion.  However, intravitreal anti-VEGF therapy has become the standard of care for DME.  Anti-inflammatory agents, such as intravitreal or sub-Tenon injections of triamcinolone acetonide and intravitreal implants of dexamethasone and fluocinolone acetonide, are also used for DME and are often effective for DME refractory to anti-VEGF therapies. Despite all the referred therapeutic modalities, there are patients who fail to respond to the treatment and do not significantly improve their visual prognosis. Moreover, these treatments have associated risks and adverse effects that should be weighted according to the expected gains. Understanding the pathophysiology of DR is therefore crucial to better adequate and allocate the available resources and to develop new alternative treatments.
As diabetic retinopathy progresses, a break-down in the blood retinal barrier (BRB) occurs causing an increase in macular vascular permeability and extravasation of plasma from blood. Resorption of the fluid elements from the extracellular space will leave lipoprotein deposits in the outer retinal layers ; these can be seen ophthalmoscopically as hard exudates. When the leakage of plasma from small macular vessels is overwhelming, accumulation of extra-cellular fluid occurs. This edema can either affect focal areas of the retina or it can diffuse throughout the posterior pole. In focal edema, leaking microaneurisms are thought to cause retinal thickening. A circinate ring of hard exudates commonly surrounds these exudating microaneurisms. In severe cases of diabetic macular edema, intraretinal leakage can occur from dilated retinal capillary bed or from intra-retinal microvascular abnormalities. When the foveal area is affected the patient usually reports blurry vision. In PDR, the formation of new blood vessels occurs from existing capillaries as a result of angiogenesis. These blood vessels usually arise in the interface between perfused and non-perfused areas of the retina in retinal neovascularization. They can also originate from the optic disk (neovascularization of the disk). These new vessels are extremely immature, fragile, permeable and bleed very easily, originating severe complications such as vitreous hemorrhage or tractional retinal detachment.
Several pathways are involved in the aforementioned processes.
Hyperglycemia and the regulation of metabolic pathways
Chronic hyperglycemia is the key promotor for the development and progression of DR due to its tissue-damaging effects. However, genetic factors may play a role in individual susceptibility to those effects and other clinical factors like hypertension, dislipidemia and pregnancy have also been implicated. 
Hyperglycemia drives the aberrant regulation of five biochemical pathways in DR patients – the polyol pathway, advanced glycation endproducts (AGEs) formation, protein kinase C (PKC) activation, hexosamine pathway flux and Poly(ADP-ribose) polymerase activation.
The Polyol Pathway
Excess glucose in RD patients is metabolized via the polyol pathway producing sorbitol. Sorbitol is impermeable to cellular membranes, accumulating inside the cell and inducing osmotic damage.  It can also be metabolized to fructose and subsequently to fructose-3-phosphate and deoxyglucosone, both of which are strong glycolyzing agents and lead to the deposition of AGEs. In addition, upregulation of the polyol pathway results in a reduced availability of NADPH, thereby enhancing the sensitivity of affected cells to oxidative stress.
Due to the high availability of glucose, AGEs formation is markedly increased in diabetic patients. AGEs have the capacity to cross-link proteins which alters their structure and function, affecting basement membranes, cellular receptors, and blood vessel wall components. Moreover, AGEs receptors activation induces prooxidant and pro-inflammatory cascades, thus exacerbating oxidative stress and leukocyte adhesion. The accumulation of AGEs has also been correlated to pericyte loss.
An increase in glycolysis activity also occurs during hyperglycemic episodes, elevating the synthesis of diacylglycerol (DAG) which in turn activates PKC pathway. PKC activates the mitogen-activated protein kinase (MAPK) factors, leading to enhanced expression of stress-related proteins and mediators of vascular function such as c-Jun kinases and heat shock proteins. In particular, the PKC-β isoform increases VEGF expression. PKC activation also drives overexpression of NADPH oxidase and NFκB in vascular cells, exacerbating oxidative stress and inflammation.
Hexosamine Pathway Flux
In the hexosamine pathway, fructose-6-phosphate (F6P) is converted into N-acetylglucosamine-6-phosphate (GlcNAc) and then into uridine-5-diphospho-N-acetylgalactosamine (UDP-GlcNAc). O-GlcNAc transferase (OGT) catalyzes the addition of GlcNAc to serine and threonine residues at phosphorylation sites on SP1, upregulating its transcriptional activity and consequently the expression of transforming growth factor beta (TGFβ) and plasminogen activator inhibitor-1 (PAI-1) in vascular cells. The glycosylation of RNA polymerase-II transcription factors by OGT and UDP-GlcNAc affects the expression of multiple factor involved in DR pathophysiology, representing a key regulatory mechanism of glucose-responsive gene transcription.
Poly(ADP-Ribose) Polymerase Activation
Hyperglycemia-induced oxidative stress correlates to increased poly(ADP-ribose) polymerase (PARP) activation. The formation of ROS leads to NAD+ depletion and inhibition of glyceraldehyde phosphate dehydrogenase (GAPDH) through the depletion of the enzyme’s catalytic cofactor and PARP-mediated ribosylation. In conjunction, these molecular mechanisms contribute to DNA damage and endothelial cell dysfunction in diabetic blood vessels.
Oxidative stress represents the common link in all of the hyperglycemia-induced biochemical and molecular pathways derangements of DR, constituting a self-amplifying cycle in which the generation of superoxide drives metabolic dysfunction and vice versa, leading to a self-perpetuating positive feedback mechanism.  Superoxide causes an elevation in the levels of glyceraldehyde-3-phosphate (G3P) by inhibiting its NAD+-dependent conversion to 1,3-diphosphoglycerate via the inhibition of GAPDH activity. G3P in turn upregulates the formation and deposition of AGEs by accelerating the addition of triose phosphates to methyl-glyoxal, the main AGE precursor. G3P also upregulates the PKC pathway by enhancing the conversion of dihydroxyacetone phosphate to DAG. G3P upregulation increases the availability of F6P which in turn drives flux through the hexosamine pathway through the enhancement of glucosamine-6-phosphate and ultimately UDP-GlcNAc levels. Finally, G3P upregulation enhances the flux through the polyol pathway by increasing the availability of glucose. The mediation of these pathways by mitochondrial superoxide is dependent on the capacity of superoxide ions to indirectly inhibit NAD+-dependent GAPDH activity, by activation of PARP and concomitant depletion of NAD+ and GAPDH ribosylation  High levels of intracellular ROS cause irreversible cell damage through epigenetic changes, such as histone modifications, DNA methylation and non-coding RNAs. Hyperglycemia derived ROS compromise function of the electron transport chain, leading to damages to mitochondrial DNA.
Chronic low-grade inflammation is a key driver of capillary occlusion and hypoxia that ultimately drives VEGF expression and concomitant hallmark vascular abnormalities that characterize DR. Leukostasis has been associated with occlusion of retinal microvasculature by monocytes and granulocytes and is spatially correlated with endothelium damage and BRB impairment in diabetic rats, contributing to endothelial cell loss and breakdown of BRB through the Fas (CD95)/Fas-ligand pathway.  This crosstalk is supported by the increase in leukocyte-endothelium adhesion molecules expression - leukocyte b2-integrins CD11a, CD11b, and CD18 and endothelial cell adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule (VCAM)-1 and E-selectin.      The relative expression of these factors is correlated to the rate of progression of DR. Chemokines have also been shown to be involved in the pathogenesis of DR. Monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein-1alpha (MIP-1α), and MIP-1β have been reported to be elevated in diabetic patients. Furthermore, inflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), IL-8 and IL-1 were significantly upregulated in diabetic patients, and their expression level was correlated with the severity of DR.  Retinal glial cell dysfunction is also presumed to be involved in inflammation in DR. Under hyperglycemic stress, microglia activation increases secretion of TNF-α, IL-6, MCP-1 and VEGF. Later involvement of Müller cells and astrocytes is associated with the amplification of inflammation responses by producing proinflammatory cytokines. Numerous studies show that inflammation inhibition by using anti-inflammatory drugs such as intravitreal triamcinolone acetonide and NSAIDs like nepafenac reduces VEGF expression and vascular permeability, inhibits retinal cell death, diminishes leukostasis, and ultimately improves visual acuity.  
Vascular abnormalities and angiogenesis pathways
Hyperglycemia causes pericyte loss, apoptosis of endothelial cells and thickening of the basement membrane, which collectively contribute to the impairment of the BRB. Since pericytes are responsible for providing structural support for capillaries, their loss leads to microaneurysm formation. Furthermore, pronounced loss of pericytes and endothelial cells results in capillary occlusion and ischemia. Retinal ischemia/hypoxia leads to upregulation of VEGF through activation of hypoxia-inducible factor 1 (HIF-1). During hypoxia, VEGFA is upregulated transcriptionally, and alternative mRNA splicing generates several VEGFA isoforms, with VEGF-165 being the most heavily implicated in DR pathology. In vascular endothelial cells, the binding of VEGFA to VEGFR2 activates the MAPK pathway and the phosphatidyl inositol 3-kinase (PI3K)/Akt pathway, promoting cell proliferation and migration and the subsequent formation of new blood vessels. Further, the VEGFA-VEGFR2 signal disrupts adherens- and tight-junctions between endothelial cells by phosphorylation of occludin and zonula occludens-1, leading to vascular hyperpermeability and fluid extravasation. Therefore, the activation of VEGFR2 by VEGFA is fundamental in PDR and DME. The renin-angiotensin-aldosterone system (RAAS) also plays a role in VEGF expression. Juxtaglomerular cells release prorenin and renin in response to the accumulation of glucose and succinate. This increases the expression of angiotensin-converting enzyme (ACE) in the retina, adversely affecting capillary perfusion and vascular structure and upregulating VEGF expression. Other angiogenic factors such as angiopoietins (Ang-1, Ang-2) and their endothelial receptor tyrosine kinase Tie2 are involved in the regulation of vascular permeability. The binding of Ang1 to Tie2 activates the PI3K/Akt pathway leading to the inactivation of a transcription factor, forkhead box O1 (FOXO1). This inactivation promotes endothelial cells survival, preventing vascular permeability, and suppressing inflammatory responses. Ang2 is upregulated in DR due to hypoxia, increased VEGFA expression, and hyperglycemia, rendering endothelial cells more sensitive to pro-angiogenic, pro-permeable, and pro-inflammatory stimuli, such as VEGFA and TNF-α.  Ang2 activates FOXO1 which in turn upregulates Ang2, forming a positive feedback loop. Extra-retinal neoangiogenesis is associated with the formation of fibrovascular membranes. However, the origin of retinal myofibroblasts is unknown in PDR. Pro-fibrotic signals, such as TGF-β, platelet-derived growth factor (PDGF) and connective tissue growth factor (CTGF), have been implicated in the transdifferentiation, proliferation, and migration of myofibroblasts and their production of contractile matrix.  Since pericytes and perivascular mesenchymal cells show the potential to transdifferentiate into myofibroblasts in various tissues and organs and given the rapid development or progression of tractional retinal detachment after injections of anti-VEGF agents into PDR eyes, it is postulated that the remaining pericytes after endothelial cells ablation from retinal neovascularization constitute a source of myofibroblasts. 
Not only vascular but also neural retina cells are affected in DR pathophysiology. In fact, retinal neurodegeneration is an early event during the progression of DR that may even precede vascular apoptosis. Upregulation of pro-apoptotic molecules such as cleaved caspase-3, Bax and Fas has been detected in retinal neurons in diabetic animals and humans.   Oxidative stress seems to be involved in the activation of these pathways, since suppression of ROS generation effectively inhibited caspase-3-mediated retinal neuronal apoptosis. Pro-apoptotic mitochondrial proteins such as cytochrome c and apoptosis-inducing factor (AIF) were also found to be significantly increased, implicating mitochondrial dysfunction in retinal degeneration  In the inner retinal layer of a mouse model of diabetes, loss of ganglion cells and reduction in retinal thickness were observed preceding the presence of microvascular alterations. In diabetic patients, inner retinal thinning was detected with no DR or minimal DR. This highlights the sensitivity of neuronal cell types to apoptotic stimuli such as oxidative stress and mitochondrial disfunction. Therefore, neuroprotective agents may play a role in preventing retinal neurodegeneration in early stages of DR. Neuronal and vascular cells interact with each other to regulate blood flow in retina via an autonomic independent mechanism. New evidence shows that this interaction is uncoupled in DR and it may assume importance in its development.
The pathophysiology of DR is not a recently discovered field in medical investigation. However, new evidence grows every day and adds up to the intricate puzzle of interactions that has already taken form. This knowledge is what opens the door to the development of treatments and to the level of quality we can find in today’s medical practice. Despite the great achievements in DR treatment, there are patients who do not respond or show suboptimal outcomes to the available therapeutics. Moreover, it is still unknown why some patients preferentially develop PDR and others DME. DR treatment is an economic burden due to the number of patients affected and the cost of anti-VEGF therapies. Therefore, filling the gaps in the landscape of DR pathophysiology is of the utmost importance for a better understanding of the disease. This review points multiples directions that are currently being pursued by the scientific community to further improve DR prevention and treatment.
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