Abstract Body: Background: Vascular inflammation is an early and potentially reversible stage of cardiopulmonary vascular disease. The pulmonary endothelium is highly vulnerable to reactive aldehydes generated by environmental exposures, but whether genetic susceptibility alters endothelial-immune communication remains unclear. We tested whether the common East Asian ALDH2*2 loss-of-function variant amplifies aldehyde-induced pulmonary vascular inflammation by disrupting endothelial barrier integrity and promoting pathological endothelial-macrophage crosstalk.
Methods: Wild-type and heterozygous ALDH2*2 knock-in mice were exposed to inhaled aldehyde-generating aerosol for 10 days. Lung histology, echocardiography, pulmonary artery wire myography, and vascular permeability assays assessed early vascular injury. Primary pulmonary vascular endothelial cells from both genotypes were exposed to acetaldehyde and analyzed for oxidative stress, viability, angiogenesis, barrier integrity, macrophage transmigration, endothelial-to-mesenchymal transition, and inflammatory transcriptomic responses. Endothelial-macrophage crosstalk was modeled using Transwell coculture.
Results: After 10 days of exposure, ALDH2*2 mice showed greater pulmonary inflammatory remodeling than wild-type mice, including increased inflammatory cell accumulation in the lung interstitium (52 ± 3 vs 25 ± 2 cells/field). ALDH2*2 mice exhibited early hemodynamic signs of oulmonary vascular inflammation. Pulmonary artery myography showed endothelial dysfunction in ALDH2*2 mice, with reduced maximal acetylcholine-induced relaxation (14.7 ± 5.4% vs 26.6 ± 3.3%) and reduced endothelin-1-induced contraction (0.16 ± 0.12 vs 0.53 ± 0.46 mN). In endothelial cells, acetaldehyde reduced ALDH2*2 viability, impaired angiogenesis, increased oxidative stress, and disrupted ZO-1 junctional integrity. Barrier disruption was associated with increased macrophage transmigration, higher macrophage IL-1β and IL-6 release, loss of PECAM1, induction of α-SMA/FSP1, and enhanced inflammatory signaling including NF-κB, TNF, leukocyte adhesion pathways, and Gas6 upregulation.
Conclusions: ALDH2*2 creates a susceptible endothelial state in which environmental aldehyde stress triggers oxidative injury, barrier disruption, macrophage recruitment, and inflammatory remodeling. These findings identify endothelial-macrophage crosstalk as a central mechanism linking impaired aldehyde detoxification to early pulmonary vascular inflammation.