Chronic Sildenafil Treatment Improves Vasomotor Function in a Mouse Model of Accelerated Aging.

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ID: 108649
2020
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Abstract
Aging leads to a loss of vasomotor control. Both vasodilation and vasoconstriction are affected. Decreased nitric oxide-cGMP-mediated relaxation is a hallmark of aging. It contributes to vascular disease, notably hypertension, infarction, and dementia. Decreased vasodilation can be caused by aging independently from cardiovascular risk factors. This process that can be mimicked in mice in an accelerated way by activation of the DNA damage response. Genetic deletion of the DNA repair enzyme ERCC1 endonuclease in mice, as in the case of mice, can be used as a tool to accelerate aging. mice develop age-dependent vasomotor dysfunction from two months after birth. In the present study we tested if chronic treatment with sildenafil, a phosphodiesterase 5 inhibitor that augments NO-cGMP signaling, can reduce the development of vasomotor dysfunction in mice. mice and wild-type littermates were treated with 10 mg/kg/d of sildenafil from the age of 6 to the age of 14 weeks. Blood pressure and in vivo and ex vivo vasomotor responses were measured at the end of the treatment period. mice developed decreased reactive hyperemia, and diminished NO-cGMP-dependent acetylcholine responses. The diminished acetylcholine response involved both endothelial and vascular smooth muscle cell signaling. Chronic sildenafil exclusively improved NO-cGMP signaling in VSMC, and had no effect on endothelium-derived hyperpolarization. Sildenafil also improved KCl hypocontractility in mice. All effects were blood pressure-independent. The findings might be of clinical importance for prevention of morbidities related to vascular aging as well as for progeria patients with a high risk of cardiovascular disease.
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golshiri2020chronicinternational Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Golshiri, Keivan;Ataei Ataabadi, Ehsan;Brandt, Renata;van der Pluijm, Ingrid;de Vries, René;Danser, Jan;Roks, Anton;
Journal International journal of molecular sciences
Year 2020
DOI
E4667
URL
Keywords
hypertension aging nitric oxide sildenafil cgmp guanylate cyclase phosphodiesterase vascular dysfunction

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