AHA Scientific Sessions 2026 Abstract · Nov 2, 2026
High Vascular Pressure Induces a Distinctive Endothelial Gene Expression Program
By Jurisch V, Schneider A, Lopez M et al.
Introduction: Hypertension is a risk factor for atherosclerosis, but the direct impact of pressure is difficult to study. We developed a mouse model in which only hemodynamic parameters differ between the two carotid arteries to identify disease drivers and validated these findings in UK Biobank data. Methods: Hypercholesterolemic mice (AAV8-PCSK9 + Western diet) were subjected to transverse aortic constriction (TAC) to induce unilateral carotid hypertension. Vascular ultrasound, histological analyses, single-cell RNA sequencing (scRNAseq) and μMACE RNA sequencing were performed at different time points. Human disease relevance was sought by relating the findings to UK Biobank data. Results: TAC induced a 123% increase in flow and accelerated atherosclerosis with fibrosis and foam cell deposition in the right carotid artery. Flow on the contralateral side decreased, and no atherosclerosis developed there. Endothelial cells (EC) on the high-pressure side acquired a turbulent flow-associated gene expression program as early as day 1 after TAC with increased Edn1, Vcam1 , and Icam1 . Trp53 expression was induced, suggesting cellular stress and apoptosis. The contralateral side exhibited a laminar flow pattern characterized by Klf2 and Klf4 expression . EC subclustering revealed 7 subpopulations with dynamic shifts over time. Pseudotime analysis demonstrated a continuum from arterial ECs to inflammatory, lipid-responsive, and ultimately EndMT-like states. This transition was accompanied by a progressive loss of arterial identity (from ~80% at day 1 to ~56% at day 70 under high-pressure conditions). A barycentric “variance triangle” was used to decompose endothelial gene expression into contributions of time, carotid location, and diet. This approach identified flow- and pressure-responsive transcription factors, including Nr4a3 , Id1 and Fosb . High activity of these factors was associated with increased expression of genes involved in EC mechanotransduction, such as Bmp4 . Endothelial μMACE analysis similarly demonstrated induction of genes associated with high flow, with Serpine1 being most prominently induced. UK Biobank analysis revealed an association of BMP4 with all-cause mortality. SERPINE1 showed strong associations with acute cardiovascular mortality, incidence of CAD and myocardial infarction in humans. Conclusion: The high-pressure, high-flow gene expression program in the right carotid artery drives atherosclerotic development and identifies predictors for vascular disease in humans.