Abstract Body: Background:
Environmental inhalation stress is increasingly recognized as an important modifier of cardiovascular disease progression. Mechanical pressure overload, characteristic of hypertension and aortic stenosis, is one of the mechanisms contributing to heart failure by inducing cardiac remodeling accompanied by lymphangiogenesis. However, the impact of inhaled pollutants on cardiac lymphatic remodeling and molecular microenvironments remains poorly understood. We assessed the hypothesis that environmental inhalation stress from electronic cigarette (ECIG) aerosols intensifies cardiac remodeling and lymphatic dysfunction during pressure-overload heart disease.
Methods:
Pressure overload heart disease model was established in mice that underwent transverse aortic constriction (TAC, n=5). Mice with sham surgery (n=5) were used as controls. Following recovery, mice were exposed to ECIG aerosols (5% nicotine in 70/30 propylene glycol and vegetable glycerin (PGVG)), PGVG vapor alone, or filtered air for 4 weeks. Cardiac lymphatic structure was evaluated by whole-mount LYVE1 staining and Prox1-GFP reporter imaging using confocal microscopy. Spatial transcriptomics was performed on heart sections to characterize myocardial cellular microenvironments.
Results:
Environmental ECIG inhalation stress triggered more lymphatic responses in TAC mice. Confocal imaging revealed increased lymphatic coverage in ECIG-exposed TAC hearts compared to PGVG and air-exposed controls. Spatial transcriptomics identified 27 cell clusters, including rare lymphatic endothelial cells (LECs). Data analysis demonstrated that ECIG exposure and TAC induce dynamic gene expression changes in lymphatic endothelial cells.
Conclusions:
Environmental inhalation stress from ECIG aerosols promotes adverse cardiac remodeling and impairs lymphatic integrity during pressure overload. Integrative imaging and spatial transcriptomics reveal structural disruption and gene expression changes within the cardiac lymphatic endothelium, highlighting a previously unrecognized lymphatic response to inhaled pollutants. Targeting inhalation-induced lymphatic dysfunction may represent a potential strategy to mitigate pollution-associated cardiac disease progression.
(The first two authors contribute evenly to this work.)