Pulmonary vascular dysfunction in ARDS Pathophysiology and therapeutic implications

Pulmonary vascular dysfunction is increasingly recognized as a clinically important component of acute respiratory distress syndrome (ARDS). Beyond alveolar epithelial injury, ARDS involves endothelial and alveolar-capillary barrier disruption, dysregulated hypoxic pulmonary vasoconstriction, thrombo-inflammatory activation, microvascular thrombosis, pulmonary vascular remodeling, increased pulmonary vascular resistance, and impaired right ventricle pulmonary circulation coupling. Together, these abnormalities aggravate ventilation perfusion mismatch, impair gas exchange, increase right ventricular afterload, and contribute to hemodynamic instability and adverse clinical outcomes. This review synthesizes current understanding of these mechanisms, critically evaluates pulmonary vascular-targeted interventions according to the strength of available evidence, and considers the clinical implications of biological and physiological heterogeneity in ARDS. Lung-protective ventilation remains the foundation of ARDS management, and early prolonged prone positioning improves outcomes in appropriately selected patients with moderate-to-severe disease. In addition to limiting lung injury and improving oxygenation, these strategies may reduce pulmonary vascular stress and right ventricular afterload. Inhaled pulmonary vasodilators can produce transient improvements in oxygenation or pulmonary hemodynamics, but no survival benefit has been established. Anticoagulant and fibrinolytic strategies, mesenchymal stromal cells, extracellular vesicles, and biologic therapies have likewise not consistently improved patient-centered outcomes and therefore remain investigational. Pulmonary vascular dysfunction nevertheless provides a clinically relevant framework for understanding gas-exchange abnormalities, cardiopulmonary interactions, and right ventricular complications in ARDS. Future studies should determine whether integrating biomarkers, pulmonary hemodynamic monitoring, imaging, respiratory mechanics, and right ventricular assessment can identify reproducible vascular, inflammatory, right ventricular, or recruitability-based phenotypes, and whether phenotype-guided pulmonary vascular management improves patient-centered outcomes.