The pulmonary microvasculature plays an essential role in maintaining alveolar integrity, but the direct effects of inhaled corticosteroids (ICS) on pulmonary endothelial cell function remain poorly understood. We investigated the effects of budesonide, formoterol, and their combination on endothelial network formation, apoptosis, migration, proliferation, and efferocytosis using human pulmonary microvascular endothelial cells (HPMEC-ST1.6R), A549 alveolar epithelial cells, and phagocytic cell models. Budesonide, alone or combined with formoterol, altered endothelial network formation on Matrigel by reducing total tubule length and the number of junctions while increasing tubule thickness, indicating reduced branching complexity. Budesonide also decreased epithelial secretion of the pro-angiogenic mediators VEGF, IL-8, and MCP-1. An independent set of experiments showed that fluticasone propionate similarly reduced VEGF, IL-8, MCP-1, TNF-alpha, and IL-6, supporting a class effect of corticosteroids on the epithelial secretome. Despite reducing angiogenic responses, budesonide protected endothelial cells from apoptosis, reduced caspase-3/7 activity, accelerated wound closure without affecting proliferation, preserved endothelial spheroid integrity, and enhanced efferocytosis. Formoterol alone had minimal effects and did not consistently enhance budesonide responses. Together, these in vitro findings suggest that, in the cell models studied, pulmonary endothelial responses to the ICS/LABA combinations tested are determined predominantly by the corticosteroid component, which suppresses pro-angiogenic mediator secretion while preserving endothelial survival and repair. As an exploratory cell-based study, these observations are hypothesis-generating and require confirmation in primary cells and in vivo models before clinical inferences can be drawn.
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