COPD: From Endothelium to New Therapies

Chronic Obstructive Pulmonary Disease (COPD) is a heterogeneous, progressive inflammatory condition of the airways and lung parenchyma, representing one of the leading causes of morbidity and mortality worldwide. Traditionally framed as a disease of airflow obstruction, COPD is now increasingly recognized as a systemic disorder in which vascular endothelial dysfunction plays a pivotal and underappreciated pathophysiological role. The pulmonary endothelium—a metabolically active monolayer lining the entire vascular tree—is critically involved in regulating vascular tone, inflammation, coagulation, and tissue remodeling. In COPD, repeated exposure to noxious stimuli, primarily cigarette smoke and air pollutants, triggers a cascade of endothelial injury mechanisms, including oxidative stress, apoptosis, cellular senescence, endothelial-to-mesenchymal transition (EndMT), and impaired angiogenesis, all of which contribute to disease progression. These mechanisms interconnect with epithelial dysfunction, systemic inflammation, cardiovascular comorbidities, and the gut–lung axis, painting a complex pathobiological picture. This review integrates current evidence on endothelial and epithelial involvement in COPD pathogenesis and bridges this knowledge with emerging and established therapeutic strategies—from inhaled bronchodilators and corticosteroids to biologics, phosphodiesterase inhibitors, ensifentrine, and novel endothelium-targeted approaches. Understanding the vascular dimension of COPD is essential to improve disease phenotyping and develop precision medicine strategies. Current limitations include the absence of approved endothelium-specific therapies for COPD and the largely preclinical or early-phase status of endothelium-targeted strategies, which restricts immediate clinical translation.