In Vivo Characterization of a Red Light-Activated Vasodilation: A Photobiomodulation Study

Abstract

Nitric oxide dependent vasodilation is an effective mechanism for restoring blood flow to ischemic tissues. Previously, we established an ex vivo murine model whereby red light (670 nm) facilitates vasodilation via an endothelium derived vasoactive species which contains a functional group that can be reduced to nitric oxide. In the present study we investigated this vasodilator in vivo by measuring blood flow with Laser Doppler Perfusion imaging in mice. The vasodilatory nitric oxide precursor was analyzed in plasma and muscle with triiodide-dependent chemiluminescence. First, a 5–10 min irradiation of a 3 cm2 area in the hind limb at 670 nm (50 mW/cm2) produced optimal vasodilation. The nitric oxide precursor in the irradiated quadriceps tissue decreased significantly from 123 ± 18 pmol/g tissue by both intensity and duration of light treatment to an average of 90 ± 17 pmol/g tissue, while stayed steady (137 ± 21 pmol/g tissue) in unexposed control hindlimb. Second, the blood flow remained elevated 30 min after termination of the light exposure. The nitric oxide precursor content significantly increased by 50% by irradiation then depleted in plasma, while remained stable in the hindlimb muscle. Third, to mimic human peripheral artery disease, an ameroid constrictor was inserted on the proximal femoral artery of mice and caused a significant reduction of flow. Repeated light treatment for 14 days achieved steady and significant increase of perfusion in the constricted limb. Our results strongly support 670 nm light can regulate dilation of conduit vessel by releasing a vasoactive nitric oxide precursor species and may offer a simple home-based therapy in the future to individuals with impaired blood flow in the leg.

Vascular Responses following Light Therapy: A Pilot Study with Healthy Volunteers

“…Light therapy in the visible range spectrum can affect photosensitive molecules, such as ATP, superoxide dismutase, or cytochrome C oxidase, which then affect the redox balance in the cells [ 11 , 12 , 13 ]. Current studies suggest that light therapy leads to an increase in mitochondrial activity, ROS production, as well as NO and, therefore, in vasodilation [ 11 , 34 , 35 , 36 ]. We did not find that light therapy had any significant effects on systolic blood pressure (SBP) or diastolic blood pressure (DPB).…”

Infrared light elicits endothelium-dependent vasodilation in isolated occipital arteries of the rat via soluble guanylyl cyclase-dependent mechanisms

“…Coupling the observations that IR-induced relaxations were largely endothelium-dependent and blocked by ODQ certainly suggests that the primary mechanism of action underlying IR-induced relaxation of the occipital artery segments involves the actions of nitric oxide/S-nitrosothiols that elicit their effects via the activation of soluble guanylate cyclase and the generation of cGMP. Red/near IR light is reported to stimulate Ca 2+ influx and Ca 2+ release from the endoplasmic reticulum ( Golovynska et al, 2020 ) degradation of preformed endothelial pools of S-nitrosothiols to nitric oxide ( Keszler et al, 2017 ; Keszler et al, 2018 ; Keszler et al, 2019 ; Weihrauch et al, 2021 ; Keszler et al, 2022 ), and release of S-nitrosothiol-containing vesicles into the interstitial space ( Riego et al, 2009 ). However, light in this wavelength has very low absorbance by water, meaning heat is not a likely mechanism.…”

“…The direct application of IR light to neural tissues can elicit a spatially selective inhibition ( Duke et al, 2013 ; Lothet et al, 2017 ), and the extracellular ion concentration can modulate the sensitivity of neural tissues to IR light ( Zhuo et al, 2021 ). There is compelling evidence that the application of red/near IR elicits endothelium-dependent vasodilation in murine facial arteries ( Keszler et al, 2017 ) and hindlimb ( Keszler et al, 2022 ), and that this vasodilation may involve the release of nitric oxide from pre-formed pools of S-nitrosothiols and/or nitrosylated proteins ( Keszler et al, 2018 ; Keszler et al, 2019 ; Weihrauch et al, 2021 ). Based on the evidence in other arteries, it may be possible that these pre-formed pools of S-nitrosothiols in murine facial arteries are stored within cytoplasmic vesicles that are subject to exocytosis ( Seckler et al, 2020 ).…”

Morphological features of the photoplethysmographic signal: a new approach to characterize the microcirculatory response to photobiomodulation

“…This bilateral response has importance in clinical practice when the area requiring treatment is not accessible or is too painful to treat. Although the vasodilative response following PBM was shown to depend on local NO synthesis or release ( Samoilova et al, 2008b ; Keszler et al, 2018 ; Weihrauch et al, 2021 ; Keszler et al, 2022 ), it has been suggested that the bilateral effect may also point to the involvement of neuronal pathways coursing through the central nervous system ( Koltzenburg et al, 1999 ) and/or the systemic release of a humoral mediator. Previous clinical studies using other interventions also observed bilateral effects where local stimulation on one side affected the other side ( Koltzenburg et al, 1999 ; Huang et al, 2007 ; Ovadia-Blechman et al, 2018 ; Ovadia-Blechman et al, 2021 ).…”

“…PBM was shown to stimulate vasodilatation and increase peripheral blood flow ( Schindl et al, 1998 ; Schindl et al, 2002 ; Samoilova et al, 2008a ; Samoilova et al, 2008b ). This effect is based at least in part on the upregulation by PBM of synthesis and secretion of nitric oxide (NO) and modification of reactive oxygen species ( Vladimirov et al, 2000 ; Chen et al, 2008 ; Gavish et al, 2008 ; Chen et al, 2022 ; Keszler et al, 2022 ). In a previous study using laser Doppler flowmetry and thermal imaging, PBM was found to increase microvascular flow ( Gavish et al, 2020 ) and that those that did not respond were found to have either ‘hot’ or ‘cold’ hand with skin temperature at baseline being >37.5°C or <33°C respectively ( Gavish et al, 2020 ).…”