title: Per2 mutation recapitulates the vascular phenotype of diabetes in the retina and bone marrow.
abstract: In this study, we assessed whether Per2 clock gene-mutant mice exhibit a vascular phenotype similar to diabetes. Per2 (B6.129-Per2(tm1Drw)/J) or wild-type control mice 4 and 12 months of age were used. To evaluate diabetes-like phenotype in Per2 mutant mice, retina was quantified for mRNA expression, and degree of diabetic retinopathy was evaluated. Bone marrow neuropathy was studied by staining femurs for tyrosine hydroxylase (TH) and neurofilament 200 (NF-200). The rate of proliferation and quantification of bone marrow progenitor cells (BMPCs) was performed, and a threefold decrease in proliferation and 50% reduction in nitric oxide levels were observed in Per2 mutant mice. TH-positive nerve processes and NF-200 staining were reduced in Per2 mutant mice. Both retinal protein and mRNA expression of endothelial nitric oxide synthase were decreased by twofold. Other endothelial function genes (VEGFR2, VEGFR1) were downregulated (1.5-2-fold) in Per2 mutant retinas, whereas there was an upregulation of profibrotic pathway mediated by transforming growth factor-β1. Our studies suggest that Per2 mutant mice recapitulate key aspects of diabetes without the metabolic abnormalities, including retinal vascular damage, neuronal loss in the bone marrow, and diminished BMPC function.
authors.affiliation: Department of Pharmacology and Therapeutics, University of Florida, Gainesville, Florida, USA.
authors.forename: Ashay D
authors.initials: AD
authors.lastname: Bhatwadekar
authors.forename: Yuanqing
authors.initials: Y
authors.lastname: Yan
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Qi
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Thinschmidt
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Neu
authors.forename: Sergio
authors.initials: S
authors.lastname: Li Calzi
authors.forename: Lynn C
authors.initials: LC
authors.lastname: Shaw
authors.forename: James M
authors.initials: JM
authors.lastname: Dominiguez
authors.forename: Julia V
authors.initials: JV
authors.lastname: Busik
authors.forename: Choogon
authors.initials: C
authors.lastname: Lee
authors.forename: Michael E
authors.initials: ME
authors.lastname: Boulton
authors.forename: Maria B
authors.initials: MB
authors.lastname: Grant
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000294:innervation* / Q000473:pathology; D002940:Circadian Rhythm; D003920:Diabetes Mellitus / Q000503:physiopathology*; D003930:Diabetic Retinopathy / Q000209:etiology*; D006412:Hematopoietic Stem Cells / Q000502:physiology; D051379:Mice; D009154:Mutation; D009569:Nitric Oxide / Q000032:analysis; D052250:Nitric Oxide Synthase Type III / Q000032:analysis; D056950:Period Circadian Proteins / Q000235:genetics / Q000502:physiology*; D010539:Permeability; D010641:Phenotype; D012160:Retina / Q000201:enzymology; D053773:Transforming Growth Factor beta1 / Q000502:physiology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000502:physiology
chemical_list: C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D053773:Transforming Growth Factor beta1; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2