The biological clock, the endothelium, and vascular remodeling Circadian rhythms are daily body rhythms that oscillate with a 24-hour period. A discrete signaling pathway termed `the biological clock'is the molecular basis of these daily rhythms. We have found that blood vessels contain a functional biological clock, including the critical clock components, Bmal1, Clock, Period, and Cryptochrome genes. Moreover, the biological clock is expressed within the endothelium of blood vessels, ideally positioned to modify endothelial signaling and vascular function. The central hypothesis of this application is that the biological clock has a local function within the vasculature to influence endothelial signaling and vascular remodeling. In the current application we present new evidence demonstrating that mice with disruption of the Bmal1 gene (Bmal1-KO), an essential component of the circadian clock, exhibit endothelial dysfunction, thrombosis, and impaired vascular remodeling. Furthermore, we demonstrate that Akt signaling, a key pathway in the regulation of endothelial function, is severely attenuated in Bmal1-KO mice. Based on these preliminary results, we hypothesize that Bmal1 is a novel regulator of endothelial signaling, vascular function, and vascular remodeling. To test this hypothesis, three specific aims are proposed. In the first aim, the regulation of the circadian clock will be studied in basal and flow-altered conditions. In the second aim, the physiologic and pathologic sequelae that impair vascular remodeling in Bmal1-KO and Clock mutant mice will be determined through analysis of blood vessel histomorphometry and cardiovascular hemodynamics. In the final aim, the molecular mechanisms through which Bmal1 regulates endothelial signaling will be determined through biochemical analysis of blood vessels in Bmal1-KO mice and in cultured endothelial cells having RNA interference to Bmal1. This work may improve our current understanding of the elevated cardiovascular risk associated with shift work, long-distance travel, and morning arousal, and provide new mechanistic insight into the development of vascular disease.

Public Health Relevance

The biological clock, the endothelium, and vascular remodeling 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. Thus, there exists a pattern of timing in cardiovascular biology and disease that follows a precise circadian rhythm. The molecular mechanism that underlies biological timing the circadian/biological clock is expressed throughout the body, including blood vessels. This work may improve our current understanding of the elevated cardiovascular risk associated with shift work, long-distance travel, and morning arousal, and provide new mechanistic insight into the development of vascular disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL089576-04
Application #
8122347
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Tolunay, Eser
Project Start
2008-08-01
Project End
2013-05-31
Budget Start
2011-06-01
Budget End
2012-05-31
Support Year
4
Fiscal Year
2011
Total Cost
$367,500
Indirect Cost
Name
Georgia Regents University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
966668691
City
Augusta
State
GA
Country
United States
Zip Code
30912
Pati, Paramita; Fulton, David J R; Bagi, Zsolt et al. (2016) Low-Salt Diet and Circadian Dysfunction Synergize to Induce Angiotensin II-Dependent Hypertension in Mice. Hypertension 67:661-8
Shang, Xia; Pati, Paramita; Anea, Ciprian B et al. (2016) Differential Regulation of BMAL1, CLOCK, and Endothelial Signaling in the Aortic Arch and Ligated Common Carotid Artery. J Vasc Res 53:269-278
Anea, Ciprian B; Zhang, Maoxiang; Chen, Feng et al. (2013) Circadian clock control of Nox4 and reactive oxygen species in the vasculature. PLoS One 8:e78626
Pandey, Deepesh; Patel, Anand; Patel, Vijay et al. (2012) Expression and functional significance of NADPH oxidase 5 (Nox5) and its splice variants in human blood vessels. Am J Physiol Heart Circ Physiol 302:H1919-28
Yu, Jun; Zhang, Yuanyuan; Zhang, Xinbo et al. (2012) Endothelium derived nitric oxide synthase negatively regulates the PDGF-survivin pathway during flow-dependent vascular remodeling. PLoS One 7:e31495
Anea, Ciprian B; Cheng, Bo; Sharma, Shruti et al. (2012) Increased superoxide and endothelial NO synthase uncoupling in blood vessels of Bmal1-knockout mice. Circ Res 111:1157-65
Chen, Feng; Yu, Yanfang; Qian, Jin et al. (2012) Opposing actions of heat shock protein 90 and 70 regulate nicotinamide adenine dinucleotide phosphate oxidase stability and reactive oxygen species production. Arterioscler Thromb Vasc Biol 32:2989-99
Cheng, Bo; Anea, Ciprian B; Yao, Lin et al. (2011) Tissue-intrinsic dysfunction of circadian clock confers transplant arteriosclerosis. Proc Natl Acad Sci U S A 108:17147-52
Pandey, Deepesh; Chen, Feng; Patel, Anand et al. (2011) SUMO1 negatively regulates reactive oxygen species production from NADPH oxidases. Arterioscler Thromb Vasc Biol 31:1634-42
Qian, Jin; Zhang, Qian; Church, Jarrod E et al. (2010) Role of local production of endothelium-derived nitric oxide on cGMP signaling and S-nitrosylation. Am J Physiol Heart Circ Physiol 298:H112-8

Showing the most recent 10 out of 18 publications