Experimental and Clinical Applications of Red and Near-Infrared Photobiomodulation on Endothelial Dysfunction: a Review

biomedicines Review Experimental and Clinical Applications of Red and Near-Infrared Photobiomodulation on Endothelial Dysfunction: A Review Esteban Colombo 1,† , Antonio Signore 1,2,†, Stefano Aicardi 3, Angelina Zekiy 4, Anatoliy Utyuzh 4, Stefano Benedicenti 1 and Andrea Amaroli 1,4,* 1 Laser Therapy Centre, Department of Surgical and Diagnostic Sciences, University of Genoa, 16132 Genoa, Italy; [email protected] (E.C.); [email protected] (A.S.); [email protected] (S.B.) 2 Department of Therapeutic Dentistry, Faculty of Dentistry, First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia 3 Department for the Earth, Environment and Life Sciences, University of Genoa, 16132 Genoa, Italy; [email protected] 4 Department of Orthopaedic Dentistry, Faculty of Dentistry, First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia; [email protected] (A.Z.); [email protected] (A.U.) * Correspondence: [email protected]; Tel.: +39-010-3537309 † These authors contributed equally to this work. Abstract: Background: Under physiological conditions, endothelial cells are the main regulator of arterial tone homeostasis and vascular growth, sensing and transducing signals between tissue Citation: Colombo, E.; Signore, A.; and blood. Disease risk factors can lead to their unbalanced homeostasis, known as endothelial Aicardi, S.; Zekiy, A.; Utyuzh, A.; dysfunction. Red and near-infrared light can interact with animal cells and modulate their metabolism Benedicenti, S.; Amaroli, A. upon interaction with mitochondria’s cytochromes, which leads to increased oxygen consumption, Experimental and Clinical Applications ATP production and ROS, as well as to regulate NO release and intracellular Ca2+ concentration. of Red and Near-Infrared This medical subject is known as photobiomodulation (PBM). We present a review of the literature Photobiomodulation on Endothelial on the in vitro and in vivo effects of PBM on endothelial dysfunction. Methods: A search strategy Dysfunction: A Review. Biomedicines was developed consistent with the PRISMA statement. The PubMed, Scopus, Cochrane, and Scholar 2021, 9, 274. https://doi.org/ 10.3390/biomedicines9030274 electronic databases were consulted to search for in vitro and in vivo studies. Results: Fifty out of >12,000 articles were selected. Conclusions: The PBM can modulate endothelial dysfunction, Academic Editor: Byeong Hwa Jeon improving inflammation, angiogenesis, and vasodilatation. Among the studies, 808 nm and 18 J (0.2 W, 2.05 cm2) intracoronary irradiation can prevent restenosis as well as 645 nm and 20 J (0.25 W, Received: 31 December 2020 2 cm2) can stimulate angiogenesis. PBM can also support hypertension cure. However, more Accepted: 5 March 2021 extensive randomised controlled trials are necessary. Published: 9 March 2021 Keywords: low-level laser therapy; phototherapy; endothelium; vascular disease; healing; angiogen- Publisher’s Note: MDPI stays neutral esis; ischemia; hypertension; inflammation; nitric oxide with regard to jurisdictional claims in published maps and institutional affil- iations. 1. Introduction An increase in the prosperity and the prevention of childhood mortality through socioeconomic and scientific progress has led to a shift, over the last two decades years, Copyright: © 2021 by the authors. from risks for infancy diseases towards those for adulthood diseases [1,2]. Licensee MDPI, Basel, Switzerland. Indeed, the main disease risk factors implicated for worldwide deaths are hyperten- This article is an open access article sion (approximately 7–18%), ischemic heart disease (approximately 5–14%), and cerebrovas- distributed under the terms and cular disease (approximately 4–14%), which are all threats of cardiovascular illness [3]. conditions of the Creative Commons The endothelium is a monolayer of endothelial cells cladding the lumen of the vascular Attribution (CC BY) license (https:// beds of the entire cardiovascular system, from the heart to the smallest capillaries. creativecommons.org/licenses/by/ 4.0/). Biomedicines 2021, 9, 274. https://doi.org/10.3390/biomedicines9030274 https://www.mdpi.com/journal/biomedicines Biomedicines 2021, 9, 274 2 of 24 It is a metabolically and mechanically dynamic organ, separating the vessel wall from the blood- and its components [4]. The endothelium, which was for a long time considered to be a relatively inert cellular monolayer, has recently been recognised as an important modulator of key physiological functions [1]. The endothelium’s role is carried out through membrane-bound receptors for hor- mones, proteins, metabolites, lipid transporting particles, as well as through specific junctional proteins and receptors that regulate cell–cell and cell-matrix interactions [5,6]. Recently, the important regulatory role of mitochondria on endothelial cells’ cyto- protective phenomena have been evidenced. In addition, stimuli affecting mitochondrial dynamics of endothelial cells can affect the production of reactive oxygen species (ROS) and adenosine triphosphate (ATP), leading to physiological or pathological response [7]. Addi- tionally, endothelial functions may also depend on changes in intracellular calcium (Ca2+) concentration, depending on depletion of Ca2+ stores and in-out-in Ca2+ signalling events, as well as multiple transient receptor potential (TRP) channel isoforms activation [8,9]. Under physiological conditions, endothelial cells are the main regulators of arterial tone homeostasis and vascular growth, sensing and transducing signals between tissue and blood [6]. Endothelial cells, through different antiplatelet and anticoagulant mechanisms, counteract thrombosis and, by regulating the expression of binding sites for procoagulant and anticoagulant agents, control the clotting system. Additionally, platelet adhesion to leukocytes represents the initial stage leading to exudation of leukocytes to inflammation or infection areas, followed by a platelet–leukocyte interaction and aggregation, and then vascular occlusion [6]. Lastly, endothelial cells, thanks to several vasoactive substances such as endothelin, angiotensin, nitric oxide (NO), vascular endothelial growth factor (VEGF), for instance, exert a regulatory role in vessel tone and growth, as well as cell proliferation and angiogenesis [1,5,6]. The dynamic features of the endothelium permit rapid response to diverse stimuli such as coagulation proteins, microbial components, shear stress, growth factors, and cytokines. These “activation” responses have evolved for host defence against microorganisms and the repair of tissue injury and are generally localised and beneficial [10]. However, this well-balanced endothelial regulation of vascular function can be af- fected by several disease risk factors, leading to both unbalanced homeostasis and an unphysiological state of healthy endothelial cells, which is known as endothelial dysfunction. As a consequence, endothelium shows reduced vasodilation induction, experiences a proinflammatory state, and prothrombic properties, which are associated with most forms of cardiovascular diseases, such as coronary artery disease, hypertension, periph- eral vascular disease, chronic heart failure, chronic kidney, diabetes, failure, and severe viral infections [10]. However, as carefully reviewed by Daiber et al. [1], the evidence that the progression of endothelial dysfunction can be counteracted and reversed increases the possibility of retarding and, in some cases, preventing the progression of the related diseases and encourages efforts to explore new therapies. Routinely, treatments applied for patient care have focused on indirect pleiotropic antioxidant properties and modulating NADPH oxidase enzymes and mitochondrial activities to prevent endothelial nitric oxide synthase (eNOS) uncoupling and stimulating anti-inflammatory effects, leading to improved endothelial function. Pharmacological agents can also be employed to equilibrate the oxidatively impaired activity of soluble guanylyl cyclase of smooth muscle [1]. In addition, mitochondria- and calcium-targeted therapeutics to counteract oxidative stress and improve endothelial dysfunction in cardiovascular disease have also been developed [11]. As fully detailed in the next paragraph, light in the red and near-infrared range of wavelength can interact with animal cells and can modulate their metabolism. Indeed, studies conducted by our research team have shown that modulation in oxygen consumption, ATP production, and ROS, after interaction of those wavelengths with mitochondrial cytochromes, as well as light, can regulate the NO release and the intracellular Ca2+ concen- Biomedicines 2021, 9, 274 3 of 24 tration [12–15]. This medical topic has been defined as low-level laser therapy, but recently, the more appropriate definition of photobiomodulation (PBM) was introduced [14]. Photobiomodulation can, thereby, counteract inflammation, stimulate growth factor expression, and modulate many cellular pathways [12,14] by different strategies, as de- scribed in the paragraph below. Therefore, PBM can support clinicians and their patients to manage and experience faster healing. In this review, we explore the ability of red and near-infrared (NIR) light to modulate cell homeostasis with particular attention to the endothelial cell line, in vitro. Additionally, the in vivo therapeutic effects of PBM on animal and human subjects are discussed. In particular, we present a review from the cell to

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