As mentioned, cannabinoids have been studied for their strong anti-inflammatory potentials and ability to inhibit/decrease various important pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α. Other than the anti-inflammatory potential, cannabinoids also have shown notable anti-angiogenic potential (Norooznezhad and Norooznezhad 2016, 2017; Norooznezhad et al. 2016; Mansouri and Norooznezhad 2019). Cannabinoids exert their biological activity through two main G protein-coupled receptors of CB1 and CB2 (Shahbazi et al. 2020). These receptors are expressed in a wide range of tissues and cells. Among the cannabinoids, some have an affinity to one or both of these receptors rendering them an agonist or antagonist potential. The CB1 receptor is expressed on smooth muscle cells of arterioles (Howlett and Abood 2017), endothelial cells (Liu et al. 2000), and certain other cells and tissues (Howlett and Abood 2017). CB2 receptor, with no psychoactive properties, has also been found on the vascular endothelial cells (Blázquez et al. 2003) as well as many other organs and tissues (Howlett and Abood 2017).

As Solinas et al., have demonstrated, CBD could inhibit endothelial cell tube formation and morphogenesis by decreasing cellular proliferation without inducing apoptosis or exerting any toxic effect. Also, one of the other inhibited pathways of angiogenesis by CBD is endothelial cells migration. In this regard, CBD has been illustrated to decrease the expression of uPA, MMP-9, PAI-1, PDGF-AA, and IL-8 (up to 50%) in human endothelial cells (Solinas et al. 2012). Furthermore, investigations have cleared that CBD could decrease vascular cell adhesion molecule-1 (VCAM-1) and intracellular adhesion molecule-1 (ICAM-1) expression, monocytes adhesion potential to endothelial cells, the endothelial barrier integrity, mitochondrial superoxide generation, and activation of NF-κB in high glucose-treated endothelial cells (Rajesh et al. 2007). Also, another study on a CBD hydroxyquinone (HU-331) showed the higher potential of this specific cannabinoid on the inhibition of angiogenesis (considering total vessel number, length, and area) induced by VEGF and FGF. HU-331 is also known to be able to decrease the von Willebrand factor (VWF) in human endothelial cells (Kogan et al. 2006). According to the studies, CBD has been identified to inhibit heparin cocktail-induced angiogenesis through suppression of VEGF and TNF-α. This agent also inhibits endothelial cell proliferation (inducing cytostasis but not apoptosis), migration, and invasion by suppressing different angiogenic factors such as PDGF, MMP-2, MMP-9, and IL-8 (Solinas et al. 2012). Also, in a viral in vivo model, CBD was demonstrated to decrease inflammation by affecting endothelial cells via VCAM-1, an endothelial-expressed protein for leukocytes transmigration (Mecha et al. 2013). It is also believed that CBD could increase the human mesenteric artery vasorelaxation. Interestingly, CBD can decrease NF-κB and phosphorylated c-Jun N-terminal kinases (JNK); thus, preventing the phosphorylation of eNOS (Stanley et al. 2015). In a diabetic model of cardiac dysfunction, CBD treatment has resulted in cardiac function improvement through inhibition of NF-κB leading to decreased VCAM-1, ICAM-1, and TNF-α expressions as well as decreasing other agents involved in oxidative stress (Rajesh et al. 2010). Altogether, it seems that other than affecting endothelial cells in the cardiovascular system, CBD could positively improve cardiac function in patients with COVID-19. Similar to its cardioprotective effects, CBD could show protective properties in other organs such as the kidney, liver, and nervous systems as well (Malinowska et al. 2021).

Endothelial cell dysfunction and some of the pro-angiogenic factors are directly associated with ARDS (Ackermann et al. 2020; Norooznezhad and Mansouri 2021). A recent in vivo study on viral infection-induced ARDS evaluated the outcomes of CBD treatment. It has been shown that CBD not only increases O₂ saturation to the normal value but also reduces IL-6, TNF-α, and INF-γ levels. Another interesting point in this study was the reduced neutrophil and increased lymphocytes count following CBD treatment (Khodadadi et al. 2020). As has been demonstrated, increased neutrophils to lymphocytes ratio (NLR) as well as lymphopenia alone are among the poor prognostic factors in patients with COVID-19 (Norooznezhad et al. 2020a; Terpos et al. 2020). Also, it has been shown that the administration of CBD has decreased pro-inflammatory cytokines (e.g. IL-6 and TNF-α) in an animal model of ARDS (Khodadadi et al. 2020). All in all, it seems that CBD could be considered as an effective treatment option functioning through the most important pathways involved in pathologic angiogenesis and endothelial cell dysfunction. Figure 1 shows some of the possible potentials of CBD on angiogenesis and endothelial dysfunction in SARS-CoV-2 infection.