The Endotheliopathy of Sepsis: Vascular Dysfunction as a Therapeutic Target

Abstract

Background- Sepsis is responsible for nearly one in five deaths worldwide, yet no targeted therapy has improved survival. Increasing evidence identifies the vascular endothelium as the organising principle of sepsis pathophysiology, integrating inflammation, coagulation, and metabolic failure into a single cascade of glycocalyx shedding, junctional disruption, coagulation imbalance, and immunothrombosis. Methods- These lesions underpin haemodynamic incoherence, acute respiratory distress syndrome, acute kidney injury, disseminated intravascular coagulation, and the long-term sequelae of post-sepsis syndrome. Circulating and urinary biomarkers—including syndecan-1, angiopoietin-2, soluble thrombomodulin, and glycosaminoglycans—mirror the extent of endothelial injury and provide translational anchors, yet remain underused in clinical classification and trial design. Result- Most vascular-targeted therapies, such as albumin, antithrombin, recombinant thrombomodulin, vitamin C, and statins, have failed to improve outcomes, largely due to unselected enrolment, delayed intervention, and reliance on crude mortality endpoints. Emerging strategies, including Tie2 agonists, angiopoietin-2 antagonists, and glycocalyx protectants, show promise but require biomarker-guided, adaptive evaluation. Reframing sepsis as endothelial failure offers a unifying paradigm for risk stratification, trial enrichment, and therapeutic innovation. Conclusion- To reduce the global burden, future strategies must be endotype-specific, mechanistically informed, and feasible across both high- and low-resource health systems.