Introduction

Ulcerative colitis (UC), one of the main forms of inflammatory bowel disease (IBD), is a chronic, progressive disorder characterized by alternating periods of relapse and remission, with a steadily increasing global prevalence.^1,2 Its long‑lasting and often severe course, apart from the typical gastrointestinal symptoms, such as abdominal pain and diarrhea, may involve numerous complications, including the need for surgical interventions, infections, anemia, nutritional deficiencies, dermatologic manifestations, joint involvement, hepatobiliary disorders, and thromboembolic events.² The disease burden is further compounded by the necessity for long‑term pharmacotherapy, repeated diagnostic evaluations—including imaging and endoscopy—and the complications arising from these procedures, ultimately resulting in a significant deterioration in patients’ overall quality of life.^2-4 Within the multifactorial etiopathogenesis and clinical course of UC, increasing attention has been directed toward endothelial dysfunction (ED). The vascular endothelium is a key regulator of multiple physiological processes, including hemostasis, angiogenesis, leukocyte migration, control of vascular permeability, and modulation of immune and inflammatory responses. ED results in impaired barrier integrity, increased permeability and leukocyte recruitment, excessive vasoconstriction, and vascular stiffness.^5,6 It can be assessed using physical methods, such as carotid intima‑media thickness (cIMT) measurement or flow‑mediated dilation (FMD), as well as through blood‑based assays.⁶ Biomarkers of endothelial injury have been increasingly utilized in inflammatory and autoimmune diseases, where they may assist in assessing the extent of vascular damage and disease activity. Consequently, biomarkers reflecting endothelial dysfunction may represent valuable tools for more precise characterization of inflammatory burden, monitoring of disease course, and identification of patients with a more severe disease phenotype. Endothelial function is regulated by multiple mechanisms and complex molecular interactions, including the interaction of cell adhesion molecules (CAMs) with corresponding integrins on leukocytes, the protective role of the endothelial glycocalyx, as well as other pathways that are increasingly explored as biomarkers of endothelial function, such as endoglin or endocan.^7-9 Among CAMs, the utility of intercellular adhesion molecule‑1 (ICAM‑1) has been demonstrated in both distinguishing patients with IBD from healthy individuals and differentiating between active and inactive disease. In contrast, data regarding vascular CAM‑1 (VCAM‑1) in IBD remain limited and inconsistent.⁷

The endothelial glycocalyx covers the luminal surface of blood vessels, and its disruption contributes to ED and inflammation. Increased circulating concentrations of soluble components of the glycocalyx, such as syndecan‑1 and hyaluronan, have been reported in various inflammatory diseases.¹⁰ Notably, in murine models of colitis, enhanced deposition of hyaluronan within the intestinal tissue has been observed during early inflammation phases, preceding leukocyte infiltration. Moreover, endothelial cells have been shown to increase hyaluronan synthesis in response to tumor necrosis factor α.¹¹

Endocan is a circulating proteoglycan secreted by endothelial cells, which participates in vascular regulation. Elevated circulating levels of endocan have been reported in several autoimmune and inflammatory disorders, suggesting its potential role as a marker of endothelial activation and injury.⁹

Data on the aforementioned biomarkers in the context of IBD are scarce. Given the growing interest in ED and the need to identify novel, easily accessible biomarkers for its assessment—with potential applications in diagnosis, disease monitoring, and therapeutic decision‑making—we conducted a study evaluating selected biomarkers of endothelial and glycocalyx injury (VCAM‑1, endocan, syndecan‑1, and hyaluronan) in patients with UC of varying disease activity, and compared the results with those of healthy controls.

Patients and methods

Results

Discussion

ED in patients with IBD is a broad topic under active investigation aimed at expanding the understanding of the disease’s pathophysiology, exploring potential applications in diagnosis, assessment of disease activity, therapeutic monitoring, drug development targeting ED pathways, and evaluation of treatment response using ED markers. One approach to assessing ED involves measuring concentrations of circulating cell adhesion molecules. The migration of immune cells across the endothelium is a complex, multistep process, initiated by interactions mediated by selectins and their ligands, followed by adhesion through members of the immunoglobulin superfamily, expressed on activated endothelial cells that bind to integrins on leukocytes. Specifically, ICAM‑1 binds to β2 integrins on leukocytes; VCAM‑1 binds to α4β1 integrins on lymphocytes, and mucosal addressin cell adhesion molecule‑1 (MAdCAM‑1) binds to α4β7 integrins on leukocytes.^6,13 The interaction between α4β7 integrin and MAdCAM‑1 is the molecular target of vedolizumab, a monoclonal antibody widely used in the biologic treatment of IBD.¹³ MAdCAM‑1 levels have been investigated for their potential utility in monitoring vedolizumab efficacy; however, current evidence is inconclusive, and no validated role for this marker in predicting or differentiating treatment response has been established.^14,15 Elevated ICAM‑1 levels have been reported in multiple studies on IBD and appear to represent a reliable marker of disease presence and activity.⁷ In contrast, VCAM‑1 has been less extensively studied, with findings suggesting both increased and decreased concentrations in IBD, leading to an unclear role in disease assessment.⁷ In our study, VCAM‑1 levels were elevated in active UC, and positively correlated with WBC and CRP. Although concentrations were higher in the patients with endoscopic activity (May score, 1–3) compared with remission (Mayo score, 0), this difference did not reach significance.

Endocan is a circulating proteoglycan secreted primarily by vascular endothelial cells, and participates in vascular regulation by stimulating the production of proinflammatory cytokines, enhancing the expression of adhesion molecules and increasing endothelial permeability.^9,16 Elevated circulating concentrations of endocan have been reported in several autoimmune and inflammatory disorders⁹; however, data on its role in IBD remain limited. In a pilot study by Voiosu et al,¹⁷ serum endocan was significantly higher in IBD patients than controls, yet no association was observed with either clinical or endoscopic activity indices. Similarly, Albayrak et al¹⁸ reported increased endocan concentrations in treatment‑naive patients with newly diagnosed UC, with a positive correlation with CRP but not with endoscopic disease activity. In contrast, our findings did not confirm elevated endocan levels in the UC patients in comparison with the controls, nor did they show differences across subgroups with varying disease activity. Although this result may initially seem unexpected, it is consistent with previous studies in which endocan concentrations showed no relationship with endoscopic severity.¹⁸ Considering that endoscopy remains the gold standard for assessing inflammatory burden, the absence of such associations may indicate a limited clinical utility of endocan as a biomarker of UC activity.

The endothelial glycocalyx is a negatively charged layer of glycoproteins and proteoglycans that covers and protects the vascular surface, comprising syndecans, biglycan, and glypican, as well as glycosaminoglycans, such as heparan sulfate, chondroitin sulfate, dermatan sulfate, keratan sulfate, and hyaluronan. Its damage contributes to ED and inflammation. Glycocalyx shedding can be assessed through soluble components, including syndecan‑1 and hyaluronan, which have been described in autoimmune and inflammatory conditions.¹⁰ Data regarding syndecan‑1 in IBD remain inconsistent. For instance, Floer et al¹⁹ demonstrated elevated syndecan‑1 concentrations in patients with active UC, whereas Mogilevski et al²⁰ reported reduced levels in active Crohn disease (CD), as compared with controls, with no significant differences across UC activity states. Evidence for hyaluronan is even more limited. In the only available IBD study, Derkacz et al²¹ reported inconclusive findings: in patients with exacerbation, hyaluronan concentrations were increased in CD 1 year after corticosteroid therapy, as compared with baseline and controls, while in UC, they were elevated only prior to adalimumab treatment in comparison with controls. Importantly, no comparisons were made between remission and active disease, which is essential for assessing the clinical value of this biomarker. In our study, syndecan‑1 showed no differences across UC activity levels, including endoscopic severity, nor correlations with other parameters. By contrast, hyaluronan was elevated in active vs inactive UC, and tended to be higher in the patients with endoscopic activity (Mayo score, 2–3; P = 0.12). However, it was not a significant predictor of UC exacerbation. Limited existing data, together with our results, highlight the need for further studies on hyaluronan in IBD to fully evaluate its potential clinical utility as a marker of disease activity.