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Abstract
Achieving reparative angiogenesis remains an unrealized goal in cardiovascular diseases. We have previously shown that deletion of the neurotrophin death receptor; p75NTR increased activation of the survival receptor; TrkA in bovine retinal endothelial cell cultures. The overall goal of this project is to examine the impact and elucidate the molecular mechanisms by which deletion of p75NTR enhances vascular repair in ischemic tissues. Using oxygen-induced retinopathy mouse model, we demonstrated that expression of p75NTR was upregulated during vaso-obliteration phase, which was accompanied by marked central vascular cell death and pathological neovascularization in WT pups. Deletion of p75NTR receptor attenuated both manifestations, a vascular protective effect that was accompanied by increased activation and expression of TrkA receptor, preservation of mature neurotrophin levels (NGF and BDNF) as well as enhanced VEGF signal. Vascular protection was reversed by intravitreal injection of the staurosporine kinase inhibitor; K-252a. Next, we assessed the impact of deleting p75NTR receptor on increasing vascular homing of mesenchymal stem cells (MSCs), using retinal ischemia- reperfusion (IR) mouse model. Trypsin-digested retinas showed that, deletion of p75NTR protected against ischemia manifested by decreased number of acellular capillaries 10 days afterIR insult. Vascular protection was enhanced by intra-vitreal injection of MSCs 48 hours after IR induction. Knocking down p75NTR receptor on the surface of MSCs increased their vascular homing to ischemic vasculature 7 days after intravitreal injection and increased SDF-1/CXCR- 4& -7 signaling axis. In summary, our results showed deletion of p75NTR receptor is protective in different retinal ischemic models. The underlying mechanism involves, at least in part, activation of the survival receptor; TrkA and increased vascular homing of MSCs. Our findings identified p75NTR receptor as novel therapeutic target for ischemic ocular diseases.