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Endothelial Dysfunction and Its Related Cardiometabolic Disorders: From Mechanisms to Targeted Therapies

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (20 February 2026) | Viewed by 15413

Special Issue Editor

Dr. Nacci Carmela

E-Mail Website
Guest Editor
Department of Precision and Regenerative Medicine and Ionian Area, School of Medicine, University of Bari «Aldo Moro», Bari, Italy
Interests: endothelial dysfunction; nitric oxide; endothelial mediators; biomarkers; adiponectin; diabetes; cardiovascular disease; inflammation; perivascular adipose tissue

Special Issue Information

Dear Colleagues,

Endothelial dysfunction represents the earliest sign of both cardiovascular and metabolic disorders, as well as a common underlying mechanism in the pathogenesis of such ailments. The renowned impact that metabolic abnormalities such as hyperglycemia, insulin resistance, hyperinsulinemia, and hyperlipidemia exert on endothelial dysfunction has been linked to pro-oxidative and pro-inflammatory mechanisms that impair endothelial cell functionality, leading to the dysregulation of the endothelial NO-synthase (eNOS) pathway. Several mechanisms may participate in eNOS dysfunctions, such as eNOS dimerization and uncoupling, modified eNOS expression/activity, the genetic polymorphism of eNOS gene, altered eNOS signaling regulation, and the epigenetic regulation of eNOS expression.

The search for specific and sensitive biomarkers of endothelial dysfunction is an ongoing actively pursued field, in which the clinical theragnostic potential extends from the validation of novel criteria for identifying at-risk subjects and monitoring the effectiveness of current treatments, to the recognition and discovery of additional therapeutic targets.

Endothelial adhesion molecules, cytokines, oxidized low density lipoproteins (Ox-LDL), circulating endothelial microparticles, and asymmetric dimethylarginine (ADMA) levels are among the putative biomarkers of endothelial activation and dysfunction that have been identified thus far. Recent evidence suggests that endothelial progenitor cell (EPC) dysfunction, alterations in the gut microbiota, and microRNA released by extracellular vesicles may also play a role in the development of cardiovascular impairment under dysmetabolic disturbances.

The goal of this Special Issue is to help to bridge the gap between molecular mechanisms involved in the onset of endothelial dysfunction and the potential therapeutic strategies targeting the pathophysiological pathways behind endothelial dysfunction and its related cardiometabolic disorders.

For this purpose, original research articles and novel review articles focusing on molecular and clinical approaches to identify predictive biomarkers are welcome.

Dr. Nacci Carmela
Guest Editor

Manuscript Submission Information

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Keywords

  • endothelial dysfunction
  • endothelial activation
  • endothelial nitric oxide synthase
  • cardiometabolic disease
  • vascular inflammation
  • chemokines
  • adipocytokines
  • atherosclerosis
  • diabetes
  • biomarkers

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Published Papers (4 papers)

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Research

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16 pages, 2268 KB  
Article
Common Biomarkers of Endothelial Dysfunction Across Highly Prevalent Diseases with Cardiovascular Risk: Functional Characterization and Prognostic Implications
by Julia Martinez-Sanchez, Sergi Torramadé-Moix, Ana Belén Moreno-Castaño, Erica Lafoz, Jordi Rovira, Fritz Diekmann, Lida Maria Rodas, Elena Cuadrado-Payán, Isabel Galceran, Aleix Cases, Ana Paula Dantas, Joan Albert Barberà, Olga Tura-Ceide, Fàtima Crispi, Eduard Gratacós, Héctor García-Calderó, Juan Carlos García-Pagán, Virginia Hernández-Gea, Gines Escolar, Arturo Pereira and Maribel Diaz-Ricartadd Show full author list remove Hide full author list
Int. J. Mol. Sci. 2026, 27(9), 3829; https://doi.org/10.3390/ijms27093829 - 25 Apr 2026
Viewed by 392
Abstract
Endothelial dysfunction (ED) arises in multiple pathologies, and its severity correlates with disease progression. Common ED biomarkers could provide prognostic value for associated complications. This study aims to identify shared ED biomarkers and assess their prognostic significance. Endothelial cells in culture (human microvascular [...] Read more.
Endothelial dysfunction (ED) arises in multiple pathologies, and its severity correlates with disease progression. Common ED biomarkers could provide prognostic value for associated complications. This study aims to identify shared ED biomarkers and assess their prognostic significance. Endothelial cells in culture (human microvascular endothelial cells, HMEC-1) were exposed to sera from patients in five disease groups (n = 20 patients/group)—liver cirrhosis with portal hypertension, idiopathic pulmonary arterial hypertension, placental disorders such as intrauterine growth restriction, coronary artery disease with acute myocardial infarction, and chronic kidney disease—or matched controls, in the absence/presence of anti-inflammatory (apixaban) and antioxidant (EUK134) compounds. We explored changes in: VCAM-1, ICAM-1, eNOS, VWF, extracellular matrix thrombogenicity, and reactive oxygen species (ROS). In serum samples, proteomics and metabolomics analyses (including lipids, amino acids, and polar metabolites) were performed through an extraction protocol to identify common ED biomarkers. Expression of VCAM-1, ICAM-1, VWF, platelet adhesion, and ROS increased in most groups versus controls (p < 0.05). Both drugs decreased all biomarker levels except eNOS (n = 6 for in vitro experiments). For serum ED biomarkers, 18 metabolites and 24 proteins showed AUC-ROC and hit rates >77.5%, and six metabolites were associated with event-free survival. These diseases share ED driven by systemic inflammatory, oxidative, and metabolic stress, are partially reversible in vitro, and are linked to biomarkers associated with clinical outcomes. Overall, ED emerges as a modifiable pathological axis with potential prognostic value. Full article
(This article belongs to the Special Issue Endothelial Dysfunction and Its Related Cardiometabolic Disorders: From Mechanisms to Targeted Therapies)
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12 pages, 706 KB  
Article
Long-Term Hemostatic and Endothelial Dysregulation Associated with Cardiovascular Events in Survivors of COVID-19 Previously Admitted to the ICU
by Raquel Behar-Lagares, Ana Virseda-Berdices, Óscar Martínez-González, Rafael Blancas, Óscar Brochado-Kith, Eva Manteiga, Paula Muñoz-García, María Jose Mallol Poyato, Jorge Molina del Pozo, Marcela Homez-Guzmán, María A. Alonso Fernández, Salvador Resino, María Á. Jiménez-Sousa and Amanda Fernández-Rodríguez
Int. J. Mol. Sci. 2025, 26(14), 6854; https://doi.org/10.3390/ijms26146854 - 17 Jul 2025
Viewed by 1240
Abstract
Post-acute sequelae of COVID-19 have been associated with an elevated risk of thromboembolism and adverse cardiovascular events (CVEs). We aim to evaluate whether alterations in poorly studied hemostatic and endothelial proteins are associated with CVEs in patients previously admitted to the ICU and [...] Read more.
Post-acute sequelae of COVID-19 have been associated with an elevated risk of thromboembolism and adverse cardiovascular events (CVEs). We aim to evaluate whether alterations in poorly studied hemostatic and endothelial proteins are associated with CVEs in patients previously admitted to the ICU and evaluated one year post-discharge. We carried out a cross-sectional study involving 63 COVID-19 patients previously admitted to the ICU one year post-discharge. Plasma levels of factor IX (coagulation factor), protein C, protein S (natural anticoagulant), and von Willebrand factor (VWF, an endothelial marker) were measured using a Luminex 200™ analyzer. Generalized linear models (GLMs) were used to assess the association of these coagulation proteins with CVEs and N-terminal pro-B-type natriuretic peptide (NT-proBNP). We found that lower levels of factor IX (p = 0.011), protein C (p = 0.028), and protein S (p = 0.008) were associated with CVEs one year after ICU discharge. Additionally, at the one-year follow-up, we found lower levels of factor IX (p = 0.002) and higher levels of VWF (p = 0.006) associated with higher levels of NT-proBNP, underscoring the involvement of both hemostatic imbalance and persistent endothelial dysfunction. Our findings revealed a gender-specific pattern of associations with NT-proBNP levels. These findings highlight the significant role of persistent hemostatic imbalance and endothelial dysfunction in the development of cardiovascular abnormalities among COVID-19 survivors discharged from the ICU. Full article
(This article belongs to the Special Issue Endothelial Dysfunction and Its Related Cardiometabolic Disorders: From Mechanisms to Targeted Therapies)
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16 pages, 1042 KB  
Article
Endothelial Dysfunction with Aging: Does Sex Matter?
by Jakub Jozue Wojtacha, Barbara Morawin, Edyta Wawrzyniak-Gramacka, Anna Tylutka, Ana Karyn Ehrenfried de Freitas and Agnieszka Zembron-Lacny
Int. J. Mol. Sci. 2024, 25(22), 12203; https://doi.org/10.3390/ijms252212203 - 13 Nov 2024
Cited by 3 | Viewed by 3388
Abstract
Oxidative stress and inflammation accompany endothelial dysfunction that results from the excessive or uncontrolled production of reactive oxygen and nitrogen species (RONS) in older adults. This study was designed to assess the usefulness of serum oxi-inflammatory component combinations in vascular disease prediction and [...] Read more.
Oxidative stress and inflammation accompany endothelial dysfunction that results from the excessive or uncontrolled production of reactive oxygen and nitrogen species (RONS) in older adults. This study was designed to assess the usefulness of serum oxi-inflammatory component combinations in vascular disease prediction and prevention with regard to sex. Women (n = 145) and men (n = 50) aged 72.2 ± 7.8 years participated in this project. The females demonstrated the elevated production of hydrogen peroxide (H2O2) and nitric oxide (NO) responsible for intravascular low-density lipoprotein oxidation. NO generation was enhanced in the women, but its bioavailability was reduced, which was expressed by a high 3-nitrotyrosine (3-NitroT) concentration. The relation of NO/3-NitroT (rs = 0.811, p < 0.001) in the women and NO/3-NitroT (rs = −0.611, p < 0.001) in the men showed that sex determines endothelial dysfunction. RONS generation in the women simultaneously promoted endothelial regeneration, as demonstrated by a ~1.5-fold increase in circulating progenitor cells. Inflammation-specific variables, such as the neutrophil-to-lymphocyte ratio, the systemic immune inflammation index, and the neutrophil-to-high-density lipoprotein (HDL) ratio, were reduced in the women and showed their diagnostic utility for clinical prognosis in vascular dysfunction, especially the C-reactive-protein-to-HDL ratio (AUC = 0.980, specificity 94.7%, sensitivity 93.3%, OR = 252, 95% CI 65–967, p < 0.001). This study is the first to have revealed sex-specific changes in the oxi-inflammatory response, which can generate the risk of cardiovascular events at an older age. Full article
(This article belongs to the Special Issue Endothelial Dysfunction and Its Related Cardiometabolic Disorders: From Mechanisms to Targeted Therapies)
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Review

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34 pages, 1239 KB  
Review
Endothelial Dysfunction as the Common Pathway Linking Obesity, Hypertension and Atherosclerosis
by Ewelina Młynarska, Kinga Bojdo, Hanna Frankenstein, Katarzyna Krawiranda, Natalia Kustosik, Wiktoria Lisińska, Jacek Rysz and Beata Franczyk
Int. J. Mol. Sci. 2025, 26(20), 10096; https://doi.org/10.3390/ijms262010096 - 16 Oct 2025
Cited by 29 | Viewed by 9235
Abstract
Endothelial dysfunction plays a central role in the pathogenesis of cardiovascular diseases, driven by a complex interplay of oxidative stress, metabolic imbalances, and adipokine dysregulation. Excessive reactive oxygen species reduce nitric oxide bioavailability by impairing endothelial nitric oxide synthase function, leading to vascular [...] Read more.
Endothelial dysfunction plays a central role in the pathogenesis of cardiovascular diseases, driven by a complex interplay of oxidative stress, metabolic imbalances, and adipokine dysregulation. Excessive reactive oxygen species reduce nitric oxide bioavailability by impairing endothelial nitric oxide synthase function, leading to vascular inflammation and impaired vasodilation. Adipose tissue-derived hormones such as leptin, adiponectin, and resistin exert opposing effects on vascular homeostasis, influencing inflammation and oxidative stress in obesity and metabolic syndrome. Dyslipidemia, particularly through oxidized LDL, initiates endothelial injury and foam cell formation, accelerating atherosclerosis. Furthermore, hypertension and obesity exacerbate vascular dysfunction by disrupting the balance between vasodilators and vasoconstrictors, enhancing oxidative stress, and altering perivascular adipose tissue function. These interrelated mechanisms contribute to the progression of atherosclerotic cardiovascular disease and diabetic vascular complications. A deeper understanding of these processes is essential for developing targeted interventions to restore endothelial health and reduce cardiometabolic risk. Full article
(This article belongs to the Special Issue Endothelial Dysfunction and Its Related Cardiometabolic Disorders: From Mechanisms to Targeted Therapies)
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