Platelet-endothelial crosstalk drives distinct endothelial dysfunction in bicuspid aortic valve disease

Background: Bicuspid aortic valves (BAV) are associated with an increased risk of premature aortic stenosis (AS). The abnormal hemodynamic conditions caused by BAV impact both platelets and valvular endothelial cells (VECs), but the contribution of platelet-derived signals to valve-specific endothelial dysfunction has not been established.

To investigate this, platelets and VECs were collected from patients with BAVs or tricuspid aortic valves (TAVs) undergoing valve replacement due to aortic stenosis. The platelets were activated to produce platelet releasate (PR), and the composition of this PR was analyzed in relation to its effects on VECs using a combination of molecular, multi-omic, functional, and computational techniques.

Results: Patients with BAV and TAV had significantly different PR profiles, which led to distinct endothelial responses. Notably, PR derived from BAV patients induced a more severe endothelial dysfunction phenotype characterized by widespread molecular reprogramming and functional alterations. A comprehensive multi-omics approach revealed that BAV PR-induced endothelial injury was primarily caused by mitochondrial dysfunction, along with activation of pathways related to endothelial remodeling, migration, and immune cell recruitment.

These molecular changes ultimately resulted in mitochondrial depolarization, altered mitochondrial dynamics, increased VEC migration, and enhanced neutrophil adhesion and chemotaxis. Computational analyses of ligand-receptor and ligand-target interactions identified potential therapeutic targets by elucidating the signaling pathways linking platelet-derived mediators to endothelial reprogramming.

The findings provide the first direct evidence that platelet activation contributes to AS initiation through the induction of endothelial dysfunction, and these effects are amplified in BAV. This discovery highlights platelet-VEC crosstalk as a novel mechanism that links abnormal valve hemodynamics to disease onset and suggests that targeting platelet-derived mediators could be a promising therapeutic strategy for AS, particularly in patients with BAV.