The electrotonic architecture of the retinal microvasculature: Diabetes-induced alteration

Abstract

Although microvascular cell death is a well established hallmark of diabetic retinopathy, which is a major cause of vision loss, much remains to be learned about the functional changes that precede the onset of morphological damage to retinal blood vessels. Early alterations of function are of interest since they may contribute to the development of irreversible pathological events. Because one of the earliest retinal effects of diabetes is the dysregulation of blood flow, we asked whether diabetes alters the functional organization of the capillary/arteriolar complex, which is the operational unit that plays an important role in regulating local perfusion. In this study, the effect of diabetes on the electrotonic architecture of the retinal microvasculature was characterized. To do this, we quantified the efficacy by which voltages are transmitted between pairs perforated-patch pipettes sealed onto abluminal cells located at well defined locations in capillary/arteriolar complexes freshly isolated from the retinas of rats made diabetic by streptozotocin. Results of these dual recording experiments were compared with data from similar experiments performed on non-diabetic retinal microvessels. These experiments revealed that diabetes caused a ~5-fold increase in the rate at which a voltage decays as it axially spreads through the retinal microvasculature. In contrast, the efficacy of radial abluminal cell/endothelial cell transmission was not significantly affected by diabetes. Based on the results of this study, which is the first to characterize how diabetes affects voltage transmission in capillary/arteriolar complexes of any tissue, we concluded that by selectively inhibiting axial transmission, diabetes alters the electrotonic architecture of the retinal microvasculature. This diabetes-induced alteration in the functional organization of the capillary/arteriolar unit is likely to impair its ability to efficiently and effectively regulate blood flow and thereby, may contribute to the progression of sight-threatening complications of diabetic retinopathy.

Dynamic connectivity maps of pericytes and endothelial cells mediate neurovascular coupling in health and disease

“…As we showed in a mouse model of diabetic retinopathy, expression of the Cx43 GJ along the vascular relay is preferentially downregulated 6, 13 . Downregulation of GJs lead to restriction of Ca2+ wave and vasomotor response experiments along the vascular branch consistent with a ~5-fold increase in voltage decays along the retinal microvasculature in rat model 56 . Disrupted vascular cell connectivity and reduced responses to vasoactive signals may contribute to decline in functional hyperemia observed early in the disease.…”

Syncytial communication in descending vasa recta includes myoendothelial coupling

“…Direct connections in cerebral vessels were described by Fujimoto (15). Parallel studies of retinal microvessels have shown robust conducted responses (41,55) that can be altered in disease states (32).…”

Retinovascular physiology and pathophysiology: New experimental approach/new insights

“…It is also feasible to transect an isolated microvascular complex at its capillary/arteriolar junction in order to determine whether an ionic current is generated in the capillary network and/or in the pre-capillary arterioles (Ishizaki et al , 2009). In addition, it is relatively straightforward to quantify the efficacy of electrotonic transmission within the retinal microvasculature by simultaneously obtaining dual perforated-patch recordings from abluminal cells located at precisely defined microvascular locations (Wu et al , 2006; Zhang et al , 2011; Nakaizumi et al , 2012). Also with isolated microvascular complexes, it is easy to quantitatively compare the amount of cell death occurring in capillaries and arterioles under pathophysiological conditions such as hypoxia (Nakaizumi & Puro, 2011).…”

“…Namely, soon after the onset of hyperglycemia, a voltage spreading axially through the endothelium of the diabetic retinal microvasculature decays at a rate that is 5-fold faster than in non-diabetic microvessels (Nakaizumi et al , 2012). As a result of this attenuation in axial transmission, locally generated voltages remain geographically delimited; the capillary/arteriolar complex would be a less interactive unit, and it appears likely that the ability of the retinal vasculature to regulate blood flow may be compromised.…”