The hypoxic tango: Neutrophil-endothelial crosstalk as master regulator of multisystem pathologies

Hypoxia, a critical pathological driver in conditions ranging from inflammatory diseases to cancer, profoundly disrupts the homeostatic interplay between neutrophils and endothelial cells. This review synthesizes current knowledge on the multifaceted mechanisms through which hypoxia, largely via the hypoxia-inducible factor (HIF) signaling axis, reprograms both cell types to create a self-perpetuating cycle of inflammation and vascular injury. We delineate how hypoxia induces a hyperactivated state in neutrophils, characterized by metabolic shifts, enhanced adhesion, a heightened secretory profile, and the release of neutrophil extracellular traps (NETs). Concurrently, hypoxia compromises endothelial barrier integrity, increases permeability, and promotes a pro-adhesive phenotype through the upregulation of adhesion molecules like E-selectin, ICAM-1, and VCAM-1. The crosstalk between these activated cells is further mediated through emerging pathways including ferroptosis and extracellular vesicle signaling. This synergistic interaction culminates in microvascular dysfunction, characterized by leukocyte stasis, capillary occlusion, and impaired tissue perfusion. By examining specific disease models—including cerebral ischemia-reperfusion injury, acute lung injury, high-altitude pulmonary edema, venous thrombosis, and neurodegenerative diseases—we highlight the central role of this dysregulated axis in disease pathogenesis. Finally, we discuss the translational implications of these findings, proposing that targeting key nodes of this interaction, such as specific adhesion cascades, NETs formation, or novel cell death pathways, offers promising therapeutic strategies for a spectrum of hypoxia-related disorders.