Objective Cardiovascular disease in SLE is not fully explained by traditional risk factors, supporting a role for disease-specific immunovascular mechanisms. Autoantibodies targeting endothelin receptor A (ET A R) and endothelin receptor B (ET B R) have been implicated in vascular injury in other autoimmune diseases, but their clinical and functional relevance in SLE remains unclear. We tested whether ET receptor autoantibodies associate with endothelial activation and directly stimulate ET receptor signalling in SLE. Methods Plasma anti-ET A R and anti-ET B R autoantibodies and soluble vascular cell adhesion molecule-1 (sVCAM-1) were measured in a pilot cohort of women with SLE and non-SLE controls and in an independent validation cohort stratified by SLE and hypertension (HTN) status. Multivariable models adjusted for demographic variables, blood pressure and medication use. Mechanistic studies were performed in primary human renal endothelial cells (HRECs) using live-cell calcium (Ca 2+ ) imaging, ET receptor antagonists and receptor-directed blocking peptides. Results Anti-ET A R and anti-ET B R autoantibodies were elevated in SLE across both cohorts, with the highest level observed in SLE with HTN. Anti-ET A R demonstrated the strongest association with sVCAM-1 and independently identified women with the highest endothelial activation burden beyond clinical covariates and anti-double-stranded DNA. In primary HRECs, SLE-derived IgG induced Ca 2+ flux that was attenuated by ET receptor antagonism. Blockade of the ET A R extracellular loop 2 domain reduced IgG-mediated Ca 2+ signalling, supporting a non-canonical mechanism of endothelial ET A R activation. Conclusions Anti-ETAR autoantibodies associate with immunovascular risk and endothelial activation in SLE and directly stimulate endothelial signalling through a non-canonical ETAR-dependent mechanism. These findings support the use of anti-ETAR autoantibodies as clinically relevant biomarkers and potential novel contributors to vascular dysfunction in SLE.
McCrorey et al. (Wed,) studied this question.