Vascular dysfunction in dengue virus infection: mechanisms, mediators and therapeutic targets

Dengue virus infection is a significant global health problem, with severe disease largely driven by vascular dysfunction during the critical phase. This review provides an overview of the current evidence on the mechanisms driving vascular hyperpermeability in dengue, with particular emphasis on endothelial dysfunction and the molecular pathways involved. Disruption of the endothelial glycocalyx is a proposed key feature in the development of severe dengue. Experimental studies identify the viral non-structural protein 1 (NS1) as a major contributor to glycocalyx degradation; however, its exact role in driving disease progression in human infection has yet to be fully established. Immune dysregulation, marked by increased production of inflammatory mediators such as tumour necrosis factor-α and interleukin-1β, contributes to endothelial barrier disruption and increased vascular permeability. During secondary heterotypic infections, antibody-dependent enhancement promotes viral uptake by Fcγ receptor-expressing immune cells, leading to increased viral replication and a heightened inflammatory response. Other factors, including mast cell activation, platelet–leukocyte interactions, angiopoietin-2 release, Toll-like receptor activation and host genetic susceptibility, also contribute to endothelial dysfunction and vascular leakage. Together, these processes lead to plasma leakage, thrombocytopenia and haemorrhage, ultimately resulting in hypotension, organ dysfunction and severe clinical outcomes. A better understanding of these mechanisms may facilitate the development of targeted therapeutic strategies. Potential therapeutic approaches focus on preserving endothelial glycocalyx integrity, limiting NS1-induced vascular permeability, stabilising mast cells and modulating inflammatory signalling. Several therapeutic agents, including ketotifen, montelukast and neuraminidase inhibitors, are currently being evaluated, while supportive fluid therapy remains the cornerstone of clinical management. A better understanding of the interactions between viral, immune and endothelial factors may support the development of more effective strategies to prevent and manage vascular complications in dengue.