Abstract
Retinal ischemia contributes to visual impairment in ischemic retinopathies. A disintegrin and metalloproteinase ADAM17 is implicated in multiple vascular pathologies through its ability to regulate inflammatory signaling via ectodomain shedding. We investigated the role of endothelial ADAM17 in neuronal and vascular degeneration associated with retinal ischemia reperfusion (IR) injury using mice with conditional inactivation of ADAM17 in vascular endothelium. ADAM17Cre-flox and control ADAM17flox mice were subjected to 40 min of pressure-induced retinal ischemia, with the contralateral eye serving as control. Albumin extravasation and retinal leukostasis were evaluated 48 h after reperfusion. Retinal morphometric analysis was conducted 7 days after reperfusion. Degenerate capillaries were assessed by elastase digest and visual function was evaluated by optokinetic test 14 and 7 days following ischemia, respectively. Lack of ADAM17 decreased vascular leakage and reduced retinal thinning and ganglion cell loss in ADAM17Cre-flox mice. Further, ADAM17Cre-flox mice exhibited a remarkable reduction in capillary degeneration following IR. Decrease in neurovascular degeneration in ADAM17Cre-flox mice correlated with decreased activation of caspase-3 and was associated with reduction in oxidative stress and retinal leukostasis. In addition, knockdown of ADAM17 resulted in decreased cleavage of p75NTR, the process known to be associated with retinal cell apoptosis. A decline in visual acuity evidenced by decrease in spatial frequency threshold observed in ADAM17flox mice was partially restored in ADAM17-endothelial deficient mice. The obtained results provide evidence that endothelial ADAM17 is an important contributor to IR-induced neurovascular damage in the retina and suggest that interventions directed at regulating ADAM17 activity can be beneficial for alleviating the consequences of retinal ischemia.
Highlights
Retinal ischemia contributes to visual impairment in ischemic retinopathies, such as diabetic retinopathy and retinopathy of prematurity, and is associated with other ocular pathologies, such as retinal vascular occlusion and acute angle-closure glaucoma [1,2,3]
We previously showed that hyperglycemia results in upregulation of retinal ADAM17 in human and experimental diabetes [35]
To verify whether ADAM17 is upregulated in retinal ischemia reperfusion (IR) model, we measured expression and enzymatic activity of this sheddase in C57Bl/6J mice subjected to ischemia followed by different periods of reperfusion
Summary
Retinal ischemia contributes to visual impairment in ischemic retinopathies, such as diabetic retinopathy and retinopathy of prematurity, and is associated with other ocular pathologies, such as retinal vascular occlusion and acute angle-closure glaucoma [1,2,3]. Neuronal cell damage is a well-described phenomenon in retinal ischemia reperfusion (IR) injury and is consistently reproduced in rodent models of retinal IR. Several research groups reported that IR recapitulates vascular impairments observed in the diabetic retina such as loss of vascular barrier function and capillary degeneration [9,10,11,12]. We sought to determine whether vascular ADAM17 contributes to cellular injury in the ischemic retina. For this purpose, we used conditional knockout mice that lack expression of ADAM17 in endothelial cells
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