ADAMTSL4 deficiency disrupts vascular smooth muscle matricellular integrity and predisposes to spontaneous coronary artery dissection

ABSTRACT: Background: Human genetic discovery studies have implicated ADAMTSL4 as a putative susceptibility locus for spontaneous coronary artery dissection (SCAD). Although biallelic ADAMTSL4 variants cause ectopia lentis via impaired fibrillin microfibril assembly the vascular consequences of heterozygous ADAMTSL4 deficiency remain unknown. Methods: We sequenced ADAMTSL4 in 568 SCAD cases and 1123 healthy controls. Protein secretion assays compared reference and SCAD-associated mutant ADAMTSL4 constructs. Human coronary artery smooth muscle cells (CASMC) with ADAMTSL4-knockdown underwent transcriptomic, proteomic, and biomechanical analyses. Ex vivo arterial ring organoids and Adamtsl4tvrm267 mutant mice were used to assess arterial integrity. Results: Rare, damaging ADAMTSL4 rare, damaging coding variants were enriched in SCAD cases compared to controls (OR=2.4[Cl:1.1-5.5],P=0.018) and gnomAD NFE N=56,885 (OR=5.0[Cl:2.8-8.2,P=9.4x10-6). In vitro, ADAMTSL4 mutant constructs showed ~50-60% reduced secretion, supporting a mechanism of extracellular ADAMTSL4 deficiency concordant with the SCAD GWAS-risk allelic effect. ADAMTL4 deficiency reduced lysyl oxidase (LOX) cross-linking activity, fibrillin microfibril biogenesis, altered huCASMC focal adhesion dynamics, whereas it increased migration and traction force, and impaired contractility, with upregulation of γ-actin-1. ADAMTSL4-deficient arterial ring organoids, and Adamtsl4tvrm267/+/Adamtsl4tvrm267/tvrm267 aortas showed reduced stiffness and failure strength, consistent with biomechanical arterial fragility and susceptibility to dissection. Conclusions: ADAMTSL4 is a critical regulator of arterial smooth muscle cell function and matrix integrity. Its genetic deficiency promotes biomechanical failure predisposing to SCAD.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Coronary Artery, Smooth Muscle Cell Of The Coronary Artery

DISEASE(S): Aortic Dissection

SUBMITTER: Cameron Pinnock  

LAB HEAD: Santhi K. Ganesh

PROVIDER: PXD083670 | Pride | 2026-10-06

REPOSITORIES: Pride