Arteriolar Involvement in the Microvascular Lesions of Diabetic Retinopathy: Implications for Pathogenesis

Abstract

Diabetic retinopathy (DR) is the most widespread complication of diabetes mellitus and a major cause of blindness in the working population of developed countries. The clinicopathology of the diabetic retina has been extensively studied, although the relative contribution of the various biochemical and molecular sequelae of hyperglycemia remains ill defined. Many neural and microvascular abnormalities occur in the retina of short-term diabetic animals but it remains uncertain how closely these acute changes relate to chronic human disease. It is important to determine the relationship between alterations observed within the first weeks or months in short-term animal models, and human disease, where clinically manifest retinopathy occurs only after durations of diabetes measured in years. This review is focused on the retinal microvasculature, although it should be appreciated that pathological changes in this system often occur in parallel with abnormalities in the neural parenchyma that may be derivative or even causal. Nevertheless, it is useful to reevaluate the microvascular lesions that are manifest in the retina during diabetes in humans and long-term animal models, since in addition to providing useful clues to the pathogenic basis of DR as a disease entity, it is in the deterrence of such changes that the efficacy of any novel treatment regimes will be measured. In particular, an emphasis will be placed on the relatively unappreciated role of arteriolar dysfunction in the clinical manifestations and pathology of this disease.

Microvascular lesions of diabetic retinopathy: clues towards understanding pathogenesis?

“…The expansion and change in protein composition of this specialized extracellular matrix is a reflection of the increased expression of vascular BM component proteins and a net reduction in proteolytic digestion. 20 There is evidence that hyperperfusion could contribute to this lesion because increased flow, in combination with raised blood viscosity, in diabetes causes endothelial responses that increase BM thickness. Shear stress is known to regulate endothelial cell gene expression through activation of multiple intracellular signalling cascades leading to expression of BM component proteins such as collagen IV, laminin, and fibronectin.…”

“…20 On the trypsin digest, these acellular capillaries appear as non-perfused naked BM tubes where the endothelial cells have disappeared. 20 Diabetes appears to greatly accelerate the turnover and renewal of retinal microvascular endothelial cells 74 and with prolonged diabetes these cells may exhaust their replicative lifespan as they exceed the so-called Hayflick limit.…”

“…20 On the trypsin digest, these acellular capillaries appear as non-perfused naked BM tubes where the endothelial cells have disappeared. 20 Diabetes appears to greatly accelerate the turnover and renewal of retinal microvascular endothelial cells 74 and with prolonged diabetes these cells may exhaust their replicative lifespan as they exceed the so-called Hayflick limit. 75 There is evidence that bone-marrow-derived endothelial progenitor cells could contribute to a compromised endothelial monolayer because these cells are also dysfunctional in diabetes, 76 as is the vessel wall they differentiate onto.…”

“…Less well recognized but equally important is the parallel demise of arterial/arteriolar VSMCs ( Figure 5) in both animal models and patients. 20 Focal and/or extensive loss of VSMCs has serious implications for arteriolar integrity and autoregulation of blood flow and may severely aggravate the retinal haemodynamic abnormalities observed in long-term diabetes. The mechanism underlying premature death of pericytes and VSMCs during diabetic retinopathy is the subject of significant research effort and a range of pathways have been identified such as oxidative stress, polyol pathway flux, activation of PKC, and accumulation of advanced AGEs.…”

“…Mild non-proliferative diabetic retinopathy (often referred to as background retinopathy) and severe proliferative retinopathy actually represent the full spectrum of the same disease process. Non-proliferative diabetic retinopathy is characterized by a complex array of vasodegenerative lesions within the retinal microvascular bed, including thickening of capillary basement membranes (BMs), pericyte and vascular smooth muscle cell (VSMC) dropout, microaneurysms, and capillary occlusion and acellularity (for a review see Gardiner et al 20 ).…”