Pathophysiology of Diabetic Retinopathy: The Old and the New

Abstract

Vision loss in diabetic retinopathy (DR) is ascribed primarily to retinal vascular abnormalities—including hyperpermeability, hypoperfusion, and neoangiogenesis—that eventually lead to anatomical and functional alterations in retinal neurons and glial cells. Recent advances in retinal imaging systems using optical coherence tomography technologies and pharmacological treatments using anti-vascular endothelial growth factor drugs and corticosteroids have revolutionized the clinical management of DR. However, the cellular and molecular mechanisms underlying the pathophysiology of DR are not fully determined, largely because hyperglycemic animal models only reproduce limited aspects of subclinical and early DR. Conversely, non-diabetic mouse models that represent the hallmark vascular disorders in DR, such as pericyte deficiency and retinal ischemia, have provided clues toward an understanding of the sequential events that are responsible for vision-impairing conditions. In this review, we summarize the clinical manifestations and treatment modalities of DR, discuss current and emerging concepts with regard to the pathophysiology of DR, and introduce perspectives on the development of new drugs, emphasizing the breakdown of the blood-retina barrier and retinal neovascularization.

Alpha-Smooth Muscle Actin-Positive Perivascular Cells in Diabetic Retina and Choroid

“…Nonetheless, topographic differences of perivascular mural cells in the normal and diseased retina have not yet been evaluated. Meanwhile, pericyte loss as pathogenesis of DR has been extensively studied, including our group [12][13][14][15][16][17], and the arteriolar VSMC alteration of DR has been established [18]. However, the αSMA positive mural cell changes in the diabetic retinal capillaries have also not been well elucidated yet.…”

Identification of Diagnostic and Prognostic microRNAs for Recurrent Vitreous Hemorrhage in Patients with Proliferative Diabetic Retinopathy

“…Ocular neoangiogenesis is a complex process defined by the formation of new blood vessels from preexisting vasculature [1,2]. This frequently occurs in diabetic retinopathy (DR), a major complication of diabetes mellitus (DM) [3]. Diabetic retinopathy is a microvascular disease in which hyperglycemia plays an important role in the pathogenesis of retinal microvascular damage.…”

“…Non-proliferative diabetic retinopathy is the early stage, where apoptosis of pericytes leads to localized microaneurysms. The progressive loss of pericytes, together with endothelial cell damage and dysfunctional capillary basement membrane, contribute to loss of the blood-retina barrier integrity, leading to intraretinal hemorrhages, exudates, and edema of the retinal tissue [3]. Vision acuity is affected when the pathology further involves the macula (i.e., diabetic macular edema) [3,4].…”

“…Ultimately, this culminates in occlusion of the lumen and/or degeneration of the capillary network, with subsequent ischemia and hypoxia of the retina. At the molecular level, the activation of hypoxia-inducible factor-1 (HIF-1) and subsequent upregulation of proangiogenic factors such as vascular endothelial growth factor (VEGF) are responsible for the impairment of the normal dynamic balance between proangiogenic and antiangiogenic factors, which leads to retinal angiogenesis [3,[5][6][7][8]. These neoangiogenic vessels lack in structural integrity, and thus have a tendency to leak and bleed, contributing to preretinal proliferative fibrovascular tissue formation [3,5,7,8].…”

“…At the molecular level, the activation of hypoxia-inducible factor-1 (HIF-1) and subsequent upregulation of proangiogenic factors such as vascular endothelial growth factor (VEGF) are responsible for the impairment of the normal dynamic balance between proangiogenic and antiangiogenic factors, which leads to retinal angiogenesis [3,[5][6][7][8]. These neoangiogenic vessels lack in structural integrity, and thus have a tendency to leak and bleed, contributing to preretinal proliferative fibrovascular tissue formation [3,5,7,8]. In advanced cases of PDR, the pathologic retinal vessel proliferation invades the vitreous body, causing sight-threatening vitreous hemorrhage (VH) and/or tractional retinal detachment [3,7,8].…”