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J Mol Cell Cardiol. 2019 Feb;127:74-82. doi: 10.1016/j.yjmcc.2018.11.014. Epub 2018 Nov 29.

Induced Trf2 deletion leads to aging vascular phenotype in mice associated with arterial telomere uncapping, senescence signaling, and oxidative stress.

Author information

1
Division of Geriatrics, Department of Internal Medicine, University of Utah School of Medicine, University of Utah, Salt Lake City, UT, USA.
2
Division of Geriatrics, Department of Internal Medicine, University of Utah School of Medicine, University of Utah, Salt Lake City, UT, USA; Geriatric Research, Education, and Clinical Center, George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, UT, USA.
3
Division of Geriatrics, Department of Internal Medicine, University of Utah School of Medicine, University of Utah, Salt Lake City, UT, USA; Geriatric Research, Education, and Clinical Center, George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, UT, USA; Department of Exercise and Sport Science, University of Utah, Salt Lake City, UT, USA.
4
Department of Human Genetics, University of Utah, Salt Lake City, UT, USA.
5
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA.
6
Division of Geriatrics, Department of Internal Medicine, University of Utah School of Medicine, University of Utah, Salt Lake City, UT, USA; Department of Geriatrics, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
7
Division of Geriatrics, Department of Internal Medicine, University of Utah School of Medicine, University of Utah, Salt Lake City, UT, USA; Geriatric Research, Education, and Clinical Center, George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, UT, USA; Department of Biochemistry, University of Utah, Salt Lake City, UT, USA; Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT, USA. Electronic address: tony.donato@utah.edu.

Abstract

Age-related vascular dysfunction in large elastic and resistance arteries is associated with reductions in microvascular perfusion and elevations in blood pressure. Recent evidence indicates that telomere uncapping-induced senescence in vascular cells may be an important source of oxidative stress and vascular dysfunction in aging, but the causal relationship between these processes has yet to be elucidated. To test this important unexplored hypothesis, we measured arterial senescence signaling and oxidative stress, carotid and mesenteric artery endothelium-dependent vasodilatory capacity, markers of mesenteric microvascular perfusion and endothelial glycocalyx deterioration, and blood pressure in a novel mouse model of Cre-inducible whole body Trf2 deletion and telomere uncapping. Trf2 deletion led to a 320% increase in arterial senescence signaling (P < .05). There was a concurrent 29% and 22% reduction in peak endothelium-dependent vasodilation in carotid and mesenteric arteries, respectively, as well as a 63% reduction in mesenteric microvascular endothelial glycocalyx thickness (all P ≤ .01). Mesenteric microvascular perfusion was reduced by 8% and systolic blood pressure was increased by 9% following Trf2 deletion (both P < .05). Trf2 deletion also led to a pro-oxidative arterial phenotype characterized by increased in NADPH oxidase gene expression; a 210% increase in superoxide levels that was partly dependent on NADPH oxidase activity; and an oxidative stress mediated reduction in carotid artery vasodilation (all P ≤ .05). Collectively, our findings demonstrate that induced Trf2 deletion leads to telomere uncapping, increased senescence signaling, and oxidative stress mediated functional impairments in the vasculature similar to those seen in human aging.

KEYWORDS:

Cellular senescence; Oxidative stress; Telomeres; Vascular aging

PMID:
30502348
DOI:
10.1016/j.yjmcc.2018.11.014
[Indexed for MEDLINE]

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