Abstract Endothelial cell (EC) injury and vascular leakage are pathological hallmarks of acute respiratory distress syndrome (ARDS), a severe form of acute lung injury (ALI) and a life-threatening condition commonly seen in critical illnesses such as severe COVID-19, pneumonia, and sepsis. The lack of effective treatments for ARDS underscores the urgent need for strategies that enhance EC regeneration and vascular repair. Perivascular macrophages (PVMs), a specialized subset of interstitial macrophages localized along the abluminal surface of blood vessels in multiple organs, have been implicated in the regulation of vascular function; however, their role in the lung in the context of ALI/ARDS remains unclear. We hypothesized that PVMs are key mediators of EC regeneration and vascular repair following lung injury. Using intravital microscopy, we captured real-time interactions between PVMs and ECs on the abluminal surface of pulmonary capillaries in live mice. Genetic depletion of PVMs in the lung resulted in increased vascular leakage and worsened outcomes following endotoxemic challenge during the acute phase of injury. In addition, PVM depletion impaired endothelial regeneration and vascular repair during the late phase of ALI compared with wild-type controls, whereas adoptive transfer of PVMs enhanced EC regeneration, improved vascular integrity, and accelerated lung recovery from ALI. Mechanistically, we found that PVMs produce extracellular vesicles (EVs) enriched in glutaminase (GLS), a key enzyme in glutamine metabolism required for cellular regeneration. PVM-derived EVs supported EC regeneration by delivering GLS and triggering a metabolic-epigenetic coupled regenerative reprogramming in ECs. In conclusion, these findings identify PVMs as critical regulators of lung vascular function that support endothelial integrity and promote vascular regeneration following injury. This work is supported by grants R01HL169447 and R01HL176717 (to B.Z.) from the National Heart, Lung, and Blood Institute. This abstract is funded by: NIH
Zhou et al. (Fri,) studied this question.