Inactivation of Endothelial ADAM17 Reduces Retinal Ischemia-Reperfusion Induced Neuronal and Vascular Damage

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.

Blue light exposure collapses the inner blood-retinal barrier by accelerating endothelial CLDN5 degradation through the disturbance of GNAZ and the activation of ADAM17

“…For example, increased ADAM17 activity has been observed in diabetic and ischemia–reperfusion-injured retinas. ADAM17 defects effectively prevent vascular leakage and alleviate neurovascular degeneration [ 48 , 49 ]. In this study, blue light initiates the activation of ADAM17.…”

ADAM10 and ADAM17—Novel Players in Retinoblastoma Carcinogenesis

“…Consistently, overexpression of ADAM17 in melanoma and hepatocellular carcinoma cells resulted in reduced apoptosis accompanied by a significant decrease in caspase-3 cleavage [ 58 , 64 ]. Moreover, ADAM17 KD in vascular endothelial cells has been shown to offer protection from retinal ischemia-reperfusion (IR) injury of ADAM17 Cre-flox mice by decreasing apoptotic cell death and active caspase-3 levels of vascular endothelial cells leading to decreased vascular degeneration [ 65 ]. Thus, ADAM17 KD during IR injury can be beneficial for preventing the consequences of ischemia in retinal tissue, which is in line with the positive influence on RB tumorigenicity seen after ADAM17 KD in retinoblastoma.…”

Elevated Plasma Soluble PD-L1 Levels in Out-of-Hospital Cardiac Arrest Patients

“…Several proteases such as matrix metalloproteinase (MMP)-9 [ 32 ], MMP-13 [ 33 ], a disintegrin and metalloproteinase (ADAM)10 [ 34 ], and ADAM17 [ 35 ] have been shown to cleave membrane-bound PD-L1, thereby forming sPD-L1. Notably, MMPs and ADAMs, including MMP-9 [ 36 ], MMP-13 [ 37 ], ADAM10 [ 38 ], and ADAM17 [ 39 ], have been shown to be activated in ischemia-reperfusion injury models. Thus, one plausible scenario is that the ischemia-reperfusion injury that occurs during CPR activates MMPs and ADAMs, which cleave off PD-L1 on leukocytes and endothelial cells to produce sPD-L1.…”