Increased potential for atherogenic changes in asthma: evidence from transcriptomic studies of arterial endothelial cells

BACKGROUND: Asthma is associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD), yet the mechanistic pathways underlying this relationship remain poorly defined. Clinical ASCVD is initiated by arterial injury, with endothelial dysfunction representing the earliest detectable stage. We aimed to characterize the differential transcriptomic response of naïve arterial endothelial cells (AECs) exposed to serum from individuals with and without asthma, using a novel stem cell-derived AEC model. METHODS: Pluripotent-derived naïve AECs were incubated with serum from individuals with asthma or healthy controls for 6 and 24 h. RNA sequencing was performed on AEC lysates, genes were compared between asthma and healthy control serum treatments, and differentially expressed genes were identified. Functional enrichment and pathway analyses were conducted using DAVID, ShinyGO, and STRING. Statistical significance was determined using false discovery rate (FDR)-adjusted p values to account for multiple comparisons. RESULTS: After 6 h of exposure to asthma serum, genes associated with biological processes of endothelial cell proliferation, angiogenesis, migration, and focal adhesion assembly (FDR-adjusted p = 0.04) were significantly enriched among upregulated genes (compared to among all genes, p = 0.0002, 0.004, and 0.04, respectively). Enriched pathways included adhesion junction, mitogen-activated protein kinase, neurotrophin, hypoxia-inducible factor-1, and Wnt signaling (p = 0.00001, 0.00004, 0.002, 0.002, 0.00001, and 0.01). At both 6 and 24 h, pathways related to lipid and atherosclerosis (p = 0.02), epidermal growth factor (EGF) receptor (p = 0.03 and 0.02 at 6 and 24 h), advanced glycation end products (AGE)-receptor for AGEs (RAGE) (p = 0.03 and 0.001), and Ras (p = 0.04 and 0.03) and Rap1 (p = 0.04 and 0.046) signaling were upregulated. Fibronectin (FN1), a central hub in the STRING network, was the highest expressed among upregulated genes at 6 h. Other central genes included EGF, vascular endothelial growth factor A and fibroblast growth factor receptor 1. CONCLUSIONS: Serum from individuals with asthma, compared to serum from healthy donors, induced gene expression alterations in a novel model of naïve AECs. These transcriptional changes are consistent with early cellular injury, including pathways of lipid-atherosclerosis, endothelial cell activation, adhesion, and AGE-RAGE signaling. These findings indicate that circulating factors in asthma activate arterial endothelial cells to promote early vascular injury.