Cardiovascular risk gene HDAC9 drives maladaptive vascular remodeling after arterial injury

Arterial restenosis following balloon angioplasty - a procedure performed to re-establish vessel patency in atherosclerotic cardiovascular disease - remains a major clinical challenge and a key barrier to durable revascularization. Endothelial denudation induced by angioplasty triggers an inflammatory cascade that drives vascular smooth muscle cell (VSMC) proliferation, migration, and phenotypic switching, culminating in neointimal hyperplasia and restenosis1. Human genetics-guided target discovery has proven more effective than non-guided approaches in revealing causal pathways of complex cardiovascular traits2. Genetic variants at Histone Deacetylase 9 (HDAC9) are a major risk factor for cardiovascular disease3,4 and is associated with increased carotid intima-media thickness and modulation of VSMC phenotype4. Here, using an experimental model of arterial injury that faithfully mirrors the vascular response to balloon angioplasty in humans, we show that HDAC9 drives maladaptive remodeling of the arterial wall following vascular injury.