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Ashay Bhatwadekar, Yanpeng Diao, Jude Al-Sabah, Sergio Caballero, Choogon Lee, Mark Segal, Maria Grant; Accelerated retinal microvasculopathy in BMAL1 deficient mice. Invest. Ophthalmol. Vis. Sci. 2013;54(15):2691.
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© ARVO (1962-2015); The Authors (2016-present)
The circadian transcription factor BMAL1 (brain and muscle ARNT-like protein) represents the positive arm of the circadian clock and is essential for the circadian clock. Mice deficient in BMAL1 have reduced lifespan and exhibit premature ageing including bone loss, organ shrinkage, monocytosis and early development of cataracts. Recently we reported that a mutation in the clock gene Per2, the negative arm of the clock, results in retinal vascular dysfunction similar to diabetic retinopathy; in this study we asked whether endothelial specific loss of clock gene Bmal1 results in similar retinal vascular phenotype and if they have a large vessel phenotype.
Whole retinas from the endothelial-specific Bmal1 mutant (Bmal1fx/fx ; Tek-cre) and wild type (WT) mice were harvested and processed to analyze mRNA expression levels of nitric oxide synthase isoforms (iNOS, eNOS) superoxide dismutase (SOD1, SOD2), and glutathione peroxidase (GPX-1) and clock genes. In parallel experiments, Bmal1fx/fx ; Tek-cre and WT mice underwent retinal microvascular injury using the ischemia-reperfusion (I/R) model. Capillary degeneration was evaluated using trypsin digestion. Endoluminal macrovascular injury was performed by introducing 0.0150 mm-diameter angioplasty guidewire into the femoral artery and the degree of neo-intimal hyperplasia was evaluated 4 weeks post-injury.
Retinas from Bmal1fx/fx;Tek-cre mice showed similar expression levels for eNOS and iNOS as compared to those in WT. In retinas from the Bmal1fx/fx;Tek-cre mice showed a marginal increase in glutathione peroxidase GPX-1, while hypoxia inducible factor 1 α and Per2 mRNA were increased 1.2 and 1.5-fold respectively compared to controls. Acellular capillaries in I/R injured retina showed a 3 fold (p<0.05) increase in number in Bmal1fx/fx;Tek-cre retinas as compared to wild type retinas. Femoral arteries of Bmal1fx/fx;Tek-cre mice showed a 20 % increase in neo-intimal hyperplasia as compared to similar injury in wild type controls.
Endothelial specific deletion of Bmal results in accelerated injury in both micro and macro vascular beds. Our study highlights critical roles of clock gene Bmal1 in maintaining normal endothelial function.
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