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Conditional Deletion of Bmal1 Accentuates Microvascular and Macrovascular Injury.

Conditional Deletion of Bmal1 Accentuates Microvascular and Macrovascular Injury.
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Bhatwadekar AD, Beli E, Yanpeng D, Chen J, Luo Q, Alex A, Caballero S, Dominguez JM, Salazar TE, Busik JV, Segal MS, Grant MB,


Bhatwadekar AD, Beli E, Yanpeng D, Chen J, Luo Q, Alex A, Caballero S, Dominguez JM, Salazar TE, Busik JV, Segal MS, Grant MB, (click to view)

Bhatwadekar AD, Beli E, Yanpeng D, Chen J, Luo Q, Alex A, Caballero S, Dominguez JM, Salazar TE, Busik JV, Segal MS, Grant MB,

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The American journal of pathology 2017 04 19() pii S0002-9440(17)30221-3
Abstract

The brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein (BMAL)-1 constitutes a major transcriptional regulator of the circadian clock. Here, we explored the impact of conditional deletion of Bmal1 in endothelium and hematopoietic cells in murine models of microvascular and macrovascular injury. We used two models of Bmal1(fx/fx);Tek-Cre mice, a retinal ischemia/reperfusion model and a neointimal hyperplasia model of the femoral artery. Eyes were enumerated for acellular capillaries and were stained for oxidative damage markers using nitrotyrosine immunohistochemistry. LSK (lineage-negative, spinocerebellar ataxia type 1 protein homolog-positive, proto-oncogene c-Kit-positive) cells were quantified and proliferation assessed. Hematopoiesis is influenced by innervation to the bone marrow, which we assessed using IHC analysis. The number of acellular capillaries increased threefold, and nitrotyrosine staining increased 1.5-fold, in the retinas of Bmal1(fx/fx);Tek-Cre mice. The number of LSK cells from the Bmal1(fx/fx);Tek-Cre mice decreased by 1.5-fold and was accompanied by a profound decrease in proliferative potential. Bmal1(fx/fx);Tek-Cre mice also exhibited evidence of bone marrow denervation, demonstrating a loss of neurofilament-200 staining. Injured femoral arteries showed a 20% increase in neointimal hyperplasia compared with similarly injured wild-type controls. Our study highlights the importance of the circadian clock in maintaining vascular homeostasis and demonstrates that specific deletion of BMAL1 in endothelial and hematopoietic cells results in phenotypic features similar to those of diabetes.

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