Conditional Deletion of Bmal1 Accentuates Microvascular and Macrovascular Injury

Ashay D Bhatwadekar, Eleni Beli, Yanpeng Diao, Jonathan Chen, Qianyi Luo, Alpha Alex, Sergio Caballero, James M Dominguez, Tatiana E Salazar, Julia V Busik, Mark S Segal, Maria B Grant

Research output: Contribution to journalArticle

6 Citations (Scopus)

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 Bmal1fx/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, stem cell antigen-1-positive, 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 Bmal1fx/fx;Tek-Cre mice. The number of LSK cells from the Bmal1fx/fx;Tek-Cre mice decreased by 1.5-fold and was accompanied by a profound decrease in proliferative potential. Bmal1fx/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.

Original languageEnglish
Pages (from-to)1426-1435
Number of pages10
JournalThe American journal of pathology
Volume187
Issue number6
Early online date19 Apr 2017
DOIs
Publication statusPublished - 01 Jun 2017
Externally publishedYes

Bibliographical note

Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Keywords

  • ARNTL Transcription Factors/deficiency
  • Animals
  • Bone Marrow/metabolism
  • Capillaries/pathology
  • Cell Proliferation
  • Circadian Rhythm/physiology
  • Disease Models, Animal
  • Endothelial Cells/metabolism
  • Femoral Artery/injuries
  • Gene Deletion
  • Hematopoietic Stem Cells/pathology
  • Hyperplasia
  • Leukocyte Common Antigens/analysis
  • Leukocyte Count
  • Mice, Transgenic
  • Neointima/pathology
  • Nitric Oxide Synthase Type III/metabolism
  • Proto-Oncogene Proteins c-akt/metabolism
  • Reperfusion Injury/metabolism
  • Retina/metabolism
  • Retinal Vessels/metabolism

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  • Cite this

    Bhatwadekar, A. D., Beli, E., Diao, Y., Chen, J., Luo, Q., Alex, A., Caballero, S., Dominguez, J. M., Salazar, T. E., Busik, J. V., Segal, M. S., & Grant, M. B. (2017). Conditional Deletion of Bmal1 Accentuates Microvascular and Macrovascular Injury. The American journal of pathology, 187(6), 1426-1435. https://doi.org/10.1016/j.ajpath.2017.02.014