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Red/near infrared light stimulates release of an endothelium dependent vasodilator and rescues vascular dysfunction in a diabetes model.

ABSTRACT: Peripheral artery disease (PAD) is a morbid condition whereby ischemic peripheral muscle causes pain and tissue breakdown. Interestingly, PAD risk factors, e.g. diabetes mellitus, cause endothelial dysfunction secondary to decreased nitric oxide (NO) levels, which could explain treatment failures. Previously, we demonstrated 670nm light (R/NIR) increased NO from nitrosyl-heme stores, therefore we hypothesized R/NIR can stimulate vasodilation in healthy and diabetic blood vessels. Vasodilation was tested by ex vivo pressure myography in wild type C57Bl/6, endothelial nitric oxide synthase (eNOS) knockout, and db/db mice (10mW/cm2 for 5min with 10min dark period). NOS inhibition with N-Nitroarginine methyl ester (L-NAME) or the NO scavenger Carboxy-PTIO (c-PTIO) tested the specificity of NO production. 4,5-Diaminofluorescein diacetate (DAF-2) measured NO in human dermal microvascular endothelial cells (HMVEC-d). R/NIR significantly increased vasodilation in wild type and NOS inhibited groups, however R/NIR dilation was totally abolished with c-PTIO and blood vessel denudation. Interestingly, the bath solution from intact R/NIR stimulated vessels could dilate light naïve vessels in a NO dependent manner. Characterization of the bath identified a NO generating substance suggestive of S-nitrosothiols or non heme iron nitrosyl complexes. Consistent with the finding of an endothelial source of NO, intracellular NO increased with R/NIR in HMVEC-d treated with and without L-NAME (1mM), yet c-PTIO (100µm) reduced NO production. R/NIR significantly dilated db/db blood vessels. In conclusion, R/NIR stimulates vasodilation by release of NO bound substances from the endothelium. In a diabetes model of endothelial dysfunction, R/NIR restores vasodilation, which lends the potential for new treatments for diabetic vascular disease.

SUBMITTER: Keszler A

PROVIDER: S-EPMC5699925 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Red/near infrared light stimulates release of an endothelium dependent vasodilator and rescues vascular dysfunction in a diabetes model.

Keszler Agnes A Lindemer Brian B Weihrauch Dorothee D Jones Deron D Hogg Neil N Lohr Nicole L NL

Free radical biology & medicine 20170919

Peripheral artery disease (PAD) is a morbid condition whereby ischemic peripheral muscle causes pain and tissue breakdown. Interestingly, PAD risk factors, e.g. diabetes mellitus, cause endothelial dysfunction secondary to decreased nitric oxide (NO) levels, which could explain treatment failures. Previously, we demonstrated 670nm light (R/NIR) increased NO from nitrosyl-heme stores, therefore we hypothesized R/NIR can stimulate vasodilation in healthy and diabetic blood vessels. Vasodilation wa ...[more]

PMID: 28935419

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Project description:The present study aimed to determine the isoform-specific role of the NADPH oxidases (NOX) in the endothelium-mediated vascular dysfunction associated with ageing. Endothelium-dependent [intraluminal flow- and acetylcholine (ACh)-induced] vasodilatation in human skeletal muscle feed arteries (SMFAs) of young (24 ± 1 years, n = 16), middle aged (45 ± 1 years, n = 18) and old (76 ± 2 years, n = 21) subjects was assessed in vitro with and without the inhibition of NOX1 (ML090), NOX2 (gp91) and NOX4 (plumbagin). To identify the role of nitric oxide (NO) bioavailability in these responses, NO synthase blockade (l-NG -monomethyl arginine citrate) was utilized. SMFA NOX1, NOX2 and NOX4 protein expression was determined by western blotting. Age related endothelium-dependent vasodilatory dysfunction was evident in response to flow (young: 69 ± 3; middle aged: 51 ± 3; old: 27 ± 3%, P < 0.05) and ACh (young: 89 ± 2; middle aged: 72 ± 3; old: 45 ± 4%, P < 0.05). NOX1 inhibition had no effect on SMFA vasodilatation, whereas NOX2 inhibition restored flow- and ACh-induced vasodilatation in the middle aged and the old SMFAs (middle aged + gp91: 69 ± 3; 86 ± 3, old + gp91: 65 ± 5; 83 ± 2%, P < 0.05) and NOX4 inhibition tended to restore these vasodilatory responses in these two groups, but neither achieved statistical significance (P ≈ 0.06). l-NG -monomethyl arginine citrate negated the restorative effects of NOX2 and NOX4 blockade. Only NOX2 and NOX4 protein expression was significantly greater in the two older groups and inversely related to vascular function (r = 0.48 to 0.93, P < 0.05). NOX2 and, to a lesser extent, NOX4 appear to play an important, probably NO-mediated, role in age-related endothelial dysfunction. KEY POINTS: The present study aimed to determine the isoform-specific role of the NADPH oxidases (NOX) in the endothelium-mediated vascular dysfunction associated with ageing. Age related endothelium-dependent vasodilatory dysfunction was evident in skeletal muscle feed arteries in response to both flow and acetylcholine. NOX2 inhibition (gp91) restored endothelium-dependent vasodilatation in the middle aged and the old skeletal muscle feed arteries, and NOX4 inhibition (plumbagin) tended to restore these vasodilatory responses in these two groups. Nitric oxide synthase inhibition negated the restorative effects of NOX2 and NOX4 blockade. NOX2 and NOX4 protein expression was significantly greater in the two older groups and inversely related to vascular function. NOX2 and, to a lesser extent, NOX4 appear to play an important, probably nitric oxide-mediated, role in age-related endothelial dysfunction and could be important therapeutic targets to maintain vascular health with ageing.

Dataset Information

Red/near infrared light stimulates release of an endothelium dependent vasodilator and rescues vascular dysfunction in a diabetes model.

Publications

Red/near infrared light stimulates release of an endothelium dependent vasodilator and rescues vascular dysfunction in a diabetes model.

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