Psoriasis is a chronic inflammatory skin disease with a reported prevalence of approximately 2% in Europe and North America, triggered and preserved by dysregulated interactions between the innate and adaptive components of the immune system (1, 2). However, cutaneous manifestations are not the only clinical demonstration of the disease. Accelerated rates of cardiovascular complications and major adverse cardiovascular events have been consistently observed in patients with psoriasis (3). Although these patients are often characterized by an unfavorable cardiometabolic profile, increased cardiovascular risk in psoriasis appears to be directly associated with the disease per se (1, 2). Pathophysiologically, central to the inflammatory hypothesis of atherosclerosis is the mutual interplay between inflammation and endothelial dysfunction, as has been described in other chronic inflammatory autoimmune disorders (4). Their synergism triggers and augments the sequence of accelerated atherosclerosis, subclinical target organ damage and eventually, clinically evident cardiovascular manifestations (4, 5).

Keeping in mind that endothelial dysfunction is considered as the earliest precursor of cardiovascular disease (CVD) (6), a thorough understanding of this process in psoriasis might commence interventions for the early identification and more effective monitoring of high-risk individuals. Therefore, the present mini review aims to provide an overall assessment of endothelial dysfunction in psoriasis, with emphasis placed on mechanisms that promote endothelial dysfunction and subsequently lead to the increased cardiovascular risk associated with the disease. Studies providing evidence of endothelial dysfunction using established as well as novel markers of endothelial dysfunction in psoriasis will be discussed. Lastly, data regarding effects of psoriasis-specific systemic treatments on endothelial dysfunction will be provided. To this end, a PubMed search was performed to identify relevant articles published in English, using the following medical terms: “psoriasis,” “endothelial dysfunction,” “cardiovascular,” and “atherosclerosis.”

Psoriasis is associated with multiple cardiometabolic diseases, which are divided into cardiovascular comorbidities and major adverse cardiovascular events (coronary heart disease, ischemic heart disease, myocardial infarction, congestive heart failure, and stroke) all of which contribute to increased cardiovascular morbidity and mortality (7, 8). The strength of this association appears to vary according to psoriasis disease severity (9). Table 1 summarizes relevant systematic reviews and meta-analyses, all of them published within the past decade, supporting the association of psoriasis with conventional cardiovascular risk factors and adverse cardiovascular events.

One crucial point is whether patients with psoriasis have an increased risk of cardiovascular events independently of -versus mediated by- their less favorable risk factor profile. At present, there is evidence for both directions. Prevalence of traditional cardiovascular risk factors is increased among patients with psoriasis compared to non-psoriasis individuals, such as ischemic heart disease, peripheral vascular disease, diabetes, hypertension, dyslipidemia, obesity and metabolic syndrome (8). In addition, several systematic reviews and meta-analyses have established the association of psoriasis with increased rates of atherosclerotic CVD. In a recent meta-analysis by Raaby et al., psoriatic patients, especially those with severe psoriasis, had an increased risk of CVDs (stroke, myocardial infarction, cardiovascular death) (10). Consistent with the above, Dhana et al. showed increased all-cause and cardiovascular mortality risk in psoriasis patients, especially those with severe psoriasis, compared to those without (11). Nevertheless, those with mild disease did not present an increased risk of cardiovascular mortality (11). More recently, increased risk of coronary artery disease was demonstrated in psoriasis by Kaiser et al., assessed by computed tomography and coronary calcium score (CCS) (12). Consequently, available epidemiological data provide solid evidence for a strong link between psoriasis and atherosclerotic CVD, which is at least partially mediated by their aggravated cardiovascular risk profile. Further experimental and clinical studies have attempted to shed light on the primary underlying pathophysiological processes eventually resulting in the establishment of clinically overt CVD independently of traditional cardiovascular factors, as described below.

Endothelial dysfunction is defined as loss of vascular dilation in response to biological and mechanical stimuli owing to the pathologic transition of the endothelium into a non-adaptive state secondary to decreased nitric oxide (NO) bioavailability (13). It is considered as a key step in the initiation and progression of atherosclerosis, the development of which involves complex interactions between the endothelium, circulating lipids, platelets, and the immune system (14–19). Several factors, including circulating proinflammatory cytokines, reactive oxygen species, oxidized LDL-C, autoantibodies and traditional cardiovascular risk factors directly and indirectly activate endothelial cells and impair their function, resulting in impaired vascular relaxation, increased leukocyte adhesion, increased endothelial permeability and generation of a pro-thrombotic state (15, 20). Importantly, all of these factors are dysregulated in psoriasis. Due to activation of immune-mediated mechanisms, the vascular endothelium presents a pro-inflammatory phenotype in psoriasis with upregulation of chemotactic, proatherogenic and vascular adhesion molecules, including tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), IL-6 and the IL-17 family of cytokines, interferon, and vascular cell adhesion molecule 1 (VCAM1). The downstream consequences result in vascular arterial inflammation and direct cytokine-induced injury (20, 21). Mechanisms of endothelial dysfunction in psoriasis are presented in Figure 1.

As the atherosclerotic procedure is being increasingly recognized as an inflammatory process, mechanisms of accelerated atherosclerosis in chronic autoimmune diseases have become a topic of growing interest (22). Pathogenetic mechanisms of CVD in psoriasis appear to be complex and have not yet been fully elucidated. However, psoriasis-triggered pathological pathways, in particular endothelial dysfunction, may activate or augment pre-existing atherosclerosis, which subsequently results in the development of clinically overt CVD (22–24).

Furthermore, chronic inflammation alters lipoproteins structurally and functionally in ways that cannot be captured through standard lipid measurements (25). Inflammation drives modification of LDL-C into small, dense particles that are known to exert pro-atherogenic effects (25). Dyslipidemia is independently associated with endothelial dysfunction, while (26, 27) lipoproteins are implicated in the generation of oxidative stress (26, 28). Oxidized LDL-C modulates NO availability through reduction of eNOS activity or by enhanced metabolism of NO by asymmetric dimethylarginine (ADMA), an endogenous competitive eNOS inhibitor (27, 29, 30). Abnormalities in lipid profile are common in psoriasis and considered to contribute substantially to endothelial dysfunction (31). Patients with psoriasis present reduced levels and efflux capacity of HDL-C, increased LDL-C particle concentration and decreased LDL-C size, as well as elevated levels of circulating PCSK9 when compared to non-psoriasis individuals (31–33).

Platelet activation is regarded as another potent mediator of endothelial dysfunction in psoriasis (34). Apart from their contribution to psoriatic skin lesions, platelets are key regulators of inflammation, immune function, and atherothrombosis. Activated platelets contribute substantially to psoriasis associated inflammation by stimulation and secretion of pro-inflammatory cytokines (18, 35). They perpetuate leukocyte recruitment, adhesion, and rolling along the activated endothelium, thereby promoting atherosclerosis and inducing endothelial dysfunction (36). Patients with psoriasis present increased circulating biomarkers of platelet activation, such as platelet-derived microvesicles, soluble p-selectin, platelet-lymphocyte and platelet-neutrophil aggregates (37). Platelets derived from psoriasis patients augment endothelial cell activation with up to a 20-fold increase in endothelial-derived cytokines such as IL-1β and IL-8 (35). In psoriasis, platelets promote IL-17 secretion from CD4+ lymphocytes, and induce in vitro endothelial injury and apoptosis when co-localized with neutrophil subtype granulocytes through the formation of neutrophil extracellular traps, a process known as NETosis (38, 39).

Lastly, although less established, other characteristic features of patients with psoriasis may contribute to the development of endothelial dysfunction. For instance, homocysteine levels are elevated in psoriasis and correlate with the severity of the disease (27). Increased homocysteine promotes oxidative stress and has been associated with the development of atherosclerosis and CVD (40, 41). In addition, insulin resistance is common in psoriasis. As a vasoactive hormone, insulin promotes vasodilation in a NO-dependent manner, increases vasodilation and presents anti-inflammatory effects (42). Likewise, adipokines appear dysregulated in patients with psoriasis, as a result of obesity which is a common comorbidity, but also independently, as they modulate cutaneous inflammation with a probable pathogenetic role in psoriasis (16). Pro-inflammatory adipokines in psoriasis may be released in the peripheral blood as a result of adipose tissue inflammation (16). Elevated adiponectin levels suppress inflammation and immune responses, whereas low adiponectin levels (including leptin, adiponectin, and resistin) are associated with endothelial dysfunction and the development of the metabolic syndrome or CVDs (16).

Considering the pathophysiological and clinical significance of endothelial dysfunction, several studies have attempted to quantify the burden of endothelial dysfunction in psoriasis, using both circulating and vascular biomarkers.

To date, topical therapies are the cornerstone for managing mild psoriasis which typically covers less than 5% body surface area (62). However, patients with moderate and severe disease, who are presumably at higher cardiovascular risk based on the above, are candidates for newer systemic therapies as first-line treatment (63, 64). The observation that these therapies could target the accompanying vascular dysfunction and ameliorate biomarkers of cardiovascular risk (65), has several therapeutic implications for cardiovascular risk prevention in psoriasis that are currently under vigorous investigation.

Psoriasis, especially in its severe forms, is an independent risk factor for cardiovascular morbidity and mortality. Several psoriasis-induced mechanisms promote the development of endothelial dysfunction, which acts synergistically with chronic inflammation and activates or potentiates pre-existing atherosclerosis in psoriasis. Available human studies using the most widely applied circulating and vascular biomarkers of endothelial dysfunction provide clinical evidence of endothelial dysfunction in patients with psoriasis, that correlates with disease severity. However, the clinical utility of biomarkers of endothelial dysfunction in psoriasis patients in terms of cardiovascular risk prediction needs to be addressed further. Moreover, it is hypothesized that effective control of the disease might improve endothelial cell function and subsequently modulate cardiovascular risk. Although some encouraging data have been published, large, prospective, appropriately designed studies are urgently warranted to provide strong evidence regarding the possibility of sustained beneficial effects on endothelial function of such therapies in psoriasis. Last but not least, future studies need to investigate whether interventions specifically targeting at the improvement of endothelial function in patients with psoriasis might provide incremental benefits in the modulation of both chronic inflammation and risk of future CVD.

EG, EL, and AP contributed to the conception and design of the study. PA and AM performed the literature searching and wrote the first draft of the manuscript. KG and MG wrote the sections of the manuscript. KG prepared the table. PA designed the figure and edited the final draft of the manuscript. EG reviewed and supervised the final version of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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