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Yuanqing Yan, Ashay D. Bhatwadekar, Michael E. Boulton, Choogon Lee, Julia V. Busik, Maria B. Grant; Circadian Dysregulation In Per2 Mutant Mice Recapitulates Diabetic Retinopathy (DR). Invest. Ophthalmol. Vis. Sci. 2011;52(14):3590.
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We have previously demonstrated that diabetic rats have dysfunctional endothelial progenitor cells (EPCs) which exhibit altered circadian rhythmicity of release from the bone marrow (BM). This defect was due to BM neuropathy which preceded the development DR. In this study, we hypothesized that in diabetes the EPC numbers within the BM would similarly be altered. Since it has been demonstrated that clock mutant mice exhibit impairment of endothelial function, similar to what is observed in diabetes, we also hypothesized that EPCs isolated from Per2 (an essential clock gene) mutant mice would show a phenotype similar to that of diabetic mice.
EPCs were quantified in BM and blood of type1 diabetic rats (~7 weeks of diabetes) using flow cytometry. Expression of clock genes, Clock, Bmal, Per1, Per2, Cry1 and Cry2 were evaluated in BM cells and retinas of control and diabetic rats. In Per 2 mutant mice, Lin-Sca1+ckit+ (LSK) (EPCs) were quantified and proliferation and mRNA levels were evaluated. BM fat content, as an indicator of the BM microenvironment, was assessed in mice using magnetic resonance spectroscopy.
EPC number showed two oscillatory peaks within the BM whereas only one peak was observed in the plasma for 12hrs. The phase and amplitude of these rhythms were severely compromised in the diabetic rats compared to controls. Expression of Cry1 and Per2 genes in the BM peaked during the active phase in control, while this was dramatically altered in diabetic rats. In Per2 mutant mice compared to wild type controls 1) the levels of EPC in the BM were reduced by 50% 2) EPC proliferation was reduced 2.5- fold 3) BM fat content was reduced 2-fold 4) mRNA levels in the retina for eNOS and FLT1 were down regulated by 2-fold (p<0.05) and the senescence gene TGFb1 was up regulated 1.8fold.
The retina and EPCs of Per2 mutant mice exhibit similar defects as those seen with diabetes suggesting that a dysfunctional clock can cause vascular dysfunction normally associated with diabetes.
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