Can endothelin A receptor autoantibodies activate endothelin signaling?

Endothelin A receptor autoantibodies (ETAR-AAs) are increasingly recognized as pathogenic drivers in cardiovascular and autoimmune diseases, acting as functional agonists rather than classic blocking antibodies.

Receptor activation and intracellular signaling

• Agonistic binding: ETAR-AAs target the second extracellular loop (ECL2) of the endothelin A receptor. This binding stabilizes the receptor in its active conformation, bypassing normal desensitization mechanisms to drive chronic, ligand-independent signaling.
• Calcium mobilization: Receptor engagement triggers canonical G-protein coupling, phospholipase C activation, and inositol-1,4,5-trisphosphate (IP3) generation, leading to sustained, pathological intracellular calcium mobilization.

Vasoconstriction and remodeling

• Pathological vasoconstriction: Downstream calcium mobilization and sensitization pathways—specifically mediated by protein kinase C (PKC) and Rho kinase (ROCK)—stimulate vascular smooth muscle cells, elevating resting vascular tone and arterial pressure.
• Maladaptive remodeling: Chronic pathway activation stimulates vascular smooth muscle cell proliferation, migration, collagen synthesis, and extracellular matrix deposition. Over time, these structural changes narrow the vessel lumen and increase wall thickness.

Endothelial dysfunction

• Barrier disruption: Pathological calcium fluxes in endothelial cells induce cytoskeletal rearrangements that disrupt adherens junctions, causing vascular hyperpermeability.
• Inflammatory activation: ETAR activation impairs nitric oxide bioavailability and upregulates key cell adhesion molecules (including VCAM-1 and ICAM-1), promoting leukocyte adhesion and chronic endothelial activation.

Bottom line

• Agonistic endothelin A receptor autoantibodies target the receptor's second extracellular loop to trigger persistent intracellular calcium signaling, directly driving pathological vasoconstriction, maladaptive structural remodeling, and endothelial barrier breakdown.