Endothelial Dysfunction and Cardiovascular Disease: Hyperbaric Oxygen Therapy as an Emerging Therapeutic Modality?

Abstract

Maintaining the physiological function of the vascular endothelium and endothelial glycocalyx is crucial for the prevention of cardiovascular disease, which is one of the leading causes of morbidity and mortality worldwide. Damage to these structures can lead to atherosclerosis, hypertension, and other cardiovascular problems, especially in individuals with risk factors such as diabetes and obesity. Endothelial dysfunction is associated with ischemic disease and has a negative impact on overall cardiovascular health. The aim of this review was to comprehensively summarize the crucial role of the vascular endothelium and glycocalyx in cardiovascular health and associated thrombo-inflammatory conditions. It highlights how endothelial dysfunction, influenced by factors such as diabetes, chronic kidney disease, and obesity, leads to adverse cardiovascular outcomes, including heart failure. Recent evidence suggests that hyperbaric oxygen therapy (HBOT) may offer therapeutic benefits in the treatment of cardiovascular risk factors and disease. This review presents the current evidence on the mechanisms by which HBOT promotes angiogenesis, shows antimicrobial and immunomodulatory effects, enhances antioxidant defenses, and stimulates stem cell activity. The latest findings on important topics will be presented, including the effects of HBOT on endothelial dysfunction, cardiac function, atherosclerosis, plaque stability, and endothelial integrity. In addition, the role of HBOT in alleviating cardiovascular risk factors such as hypertension, aging, obesity, and glucose metabolism regulation is discussed, along with its impact on inflammation in cardiovascular disease and its potential benefit in ischemia-reperfusion injury. While HBOT demonstrates significant therapeutic potential, the review also addresses potential risks associated with excessive oxidative stress and oxygen toxicity. By combining information on the molecular mechanisms of HBOT and its effects on the maintenance of vascular homeostasis, this review provides valuable insights into the development of innovative therapeutic strategies aimed at protecting and restoring endothelial function to prevent and treat cardiovascular diseases.

Keywords: cardiovascular diseases; endothelial dysfunction; endothelial glycocalyx; endothelium; hyperbaric oxygen therapy.

Figure 1

Schematic representation of endothelial glycocalyx structure. MMP–matrix metalloproteinases.

Figure 2

Key effects of a therapeutic intervention across six biological pathways: Angiogenesis stimulation encourages new blood vessel growth through molecules like nitric oxide (NO), vascular endothelial growth factor (VEGF), and growth factors (GFs) such as platelet-derived growth factor (PDGF-2) and fibroblast growth factor (FGF-2), which help repair and regenerate tissues. Inflammation alleviation reduces inflammation by increasing anti-inflammatory cytokines [e.g., interleukins (IL-4, IL-10)] and lowering pro-inflammatory molecules [e.g., cyclooxygenase-2 (COX-2) and tumor necrosis factor alpha (TNF-α)], aiding immune regulation and reducing tissue damage. Antimicrobial activity boosts the body’s ability to kill anaerobic bacteria and reduces biofilm formation, enhancing resistance to infections. Cellular senescence suppression slows down the aging process by downregulating markers of cellular senescence (e.g., senescence-associated β-galactosidase (SA-β-gal) and cellular senescence markers (p16/p21/p53)) and promoting telomere elongation, which helps cells avoid age-related dysfunction and re-enter the cell cycle. Stem cell stimulation increases the number of circulating stem cells, promoting their differentiation into various tissue types like adipose cells and osteocytes, thus supporting tissue regeneration and healing. Elevation of antioxidant activity enhances antioxidant defenses by modulating the balance between free radicals and scavengers, protecting cells from oxidative stress and damage, which is crucial for maintaining cellular health.

Figure 3

The tissue response to hypoxia and repeated intermittent hyperoxia during hyperbaric oxygen therapy (HBOT) results in a biphasic response and involves an accumulation of reactive oxygen species (ROS) alongside an enhanced cytoprotective antioxidant response. Hypoxia and intermittent HBOT promote the activation of hypoxia-inducible factor-1 (HIF-1), either by directly inhibiting prolyl hydroxylase domains (PHDs) or by increasing antioxidants that suppress PHD activity. During hyperoxia, ROS production increases, leading to the activation of HIF-1α, which conjugates with HIF-1β to stabilize HIF-1 in its active form. HIF-1, in turn, inhibits mitochondrial biogenesis. Increased mitochondrial consumption of NADH raises NAD+ levels, which activates SIRT1, improving mitochondrial biogenesis and inducing antioxidant defenses. As part of an adaptive mechanism, elevated ROS levels stimulate the production of endogenous scavengers, whose elimination half-life is significantly longer than that of ROS. Additionally, HBOT enhances antioxidant enzyme levels by activating transcription factors and gene expression via the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway and its downstream targets, including heme oxygenase-1 (HO-1), NAD(P)H quinone dehydrogenase 1 (NQO-1), catalase (CAT), glutathione peroxidase (GPx), superoxide dismutase (SOD), and glutamate–cysteine ligase catalytic subunit (GCLC), while reducing pro-oxidant enzymes such as inducible nitric oxide synthase (iNOS) and gp91-phox.

Figure 4

The effect of hyperbaric oxygen therapy (HBOT) on oxidative stress balance at the level of the mitochondrial membrane. In HBOT, oxygen from the lungs increases the content of oxygen dissolved in the plasma, resulting in tissue hyperoxia that boosts the citric acid cycle in mitochondria, increasing nicotinamide adenine dinucleotide (NADH) production, which can react directly with oxygen to produce reactive oxygen species (ROS). Increased ROS levels can produce more endogenous scavengers, with the elimination half-life being much longer than that of ROS. HBOT stimulates antioxidant defenses via activation of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream targets such as heme oxygenase-1 (HO-1), NAD(P)H quinone dehydrogenase 1 (NQO-1), catalase (CAT), glutathione peroxidase (GPx), superoxide dismutase (SOD), and glutamate–cysteine ligase catalytic subunit (GCLC), while decreasing expression of pro-oxidant enzymes such as inducible nitric oxide synthase (iNOS) and gp91-phox.