Abstract 1167: A Path To Vascular Disease Through The Biological Clock

Abstract

Cardiovascular disease is the leading cause of death for both men and women in the United States and the world. There is a profound pattern in the time of day at which the death occurs; it is in the morning, when the endothelium is most vulnerable and blood pressure surges, that stroke and heart attack most frequently happen. Though the biological clock rhythmically oscillates in blood vessels, evidence of a direct function in the vasculature for Bmal1, an essential clock component, is lacking. We have found that chronic flow interruption in arteries of mice with targeted disruption of Bmal1 gene (Bmal1-KO) causes pathological vascular remodeling which worsens to thrombosis with ageing. In addition, naïve aortic arteries of Bmal1-KO mice exhibit endothelial dysfunction, which is improved by relief of oxidant stress. Akt signalling, a pathway critical to vascular function, was significantly attenuated in arteries of Bmal1-KO mice. Co-transfection of cultured cells with the transcription factors Bmal-Npas2 or Bmal1-Clock induced a robust activation of the Akt promoter, providing evidence of a direct link between the circadian clock and Akt pathways. Our data reveals a new role for the biological clock in the control of endothelial signalling and vascular remodeling which may be of significant impact in the progression of vascular disease.