Evaluation of < b > < i > Notch3 < /i > < /b > Deficiency in Diabetes-Induced Pericyte Loss in the Retina

Loss of vascular pericytes has long been associated with the onset of diabetic retinopathy; however, mechanisms contributing to pericyte dropout are not understood.Notch3 has been implicated in pericyte stability and survival, and linked to vascular integrity.Notch3 mutant mice exhibit progressive loss of retinal pericytes. Given that diabetic retinopathy is associated with pericyte loss, we sought to determine whether perturbation ofNotch3 signaling contributes to diabetes-induced pericyte dropout and capillary degeneration. We utilized a pericyte-expressed LacZ transgene (XlacZ4) to examine pericyte loss in retinas of a type I diabetic mouse model (Ins2Akita) andNotch3-deficient mice.Notch3 null animals showed a dramatic loss of the LacZ marker by 8 weeks of age, whileIns2Akita diabetic andNotch3 heterozygous mice exhibited a much slower and subtler loss of LacZ. Although combinedNotch3 heterozygosity inIns2Akita diabetic animals did not show further deficits, the trypsin digest method revealed thatNotch3 haploinsufficiency increased the formation of acellular capillaries in diabetic mice. Our data further indicate that Notch signaling is blunted in diabetic retinas and in cells exposed to hyperglycemia. These results are the first to demonstrate an association betweenNotch3 signaling, pericyte loss, and diabetic retinopathy.J Vasc Res 2018;55:308 –318

Source: Journal of Vascular Research - October 24, 2018 Category: Research Source Type: research