Endothelial dysfunction, impaired angiogenesis and cellular senescence in type 2 diabetes\nconstitute dominant risk factors for chronic non-healing wounds and other cardiovascular disorders.\nStudying these phenomena in the context of diabetes and the TSP1-CD-47 signaling dictated the use\nof the in vitro wound endothelial cultured system and an in vivo PVA sponge model of angiogenesis.\nHerein we report that diabetes impaired the in vivo sponge angiogenic capacity by decreasing cell\nproliferation, fibrovascular invasion and capillary density. In contrast, a heightened state of oxidative\nstress and elevated expression of TSP1 and CD47 both at the mRNA and protein levels were evident\nin this diabetic sponge model of wound healing. An in vitro culturing system involving wound\nendothelial cells confirmed the increase in ROS generation and the up-regulation of TSP1-CD47\nsignaling as a function of diabetes. We also provided evidence that diabetic wound endothelial\ncells (W-ECs) exhibited a characteristic feature that is consistent with cellular senescence. Indeed,\nenhanced SA-Beta-gal activity, cell cycle arrest, increased cell cycle inhibitors (CKIs) p53, p21 and p16\nand decreased cell cycle promoters including Cyclin D1 and CDK4/6 were all demonstrated in these\ncells. The functional consequence of this cascade of events was illustrated by a marked reduction\nin diabetic endothelial cell proliferation, migration and tube formation. A genetic-based strategy\nin diabetic W-ECs using CD47 siRNA significantly ameliorated in these cells the excessiveness in\noxidative stress, attenuation in angiogenic potential and more importantly the inhibition in cell cycle\nprogression and its companion cellular senescence. To this end, the current data provide evidence\nlinking the overexpression of TSP1-CD47 signaling in diabetes to a number of parameters associated\nwith endothelial dysfunction including impaired angiogenesis, cellular senescence and a heightened\nstate of oxidative stress. Moreover, it may also point to TSP1-CD47 as a potential therapeutic target in\nthe treatment of the aforementioned pathologies.
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