SVEP1 is an endogenous ligand for the orphan receptor PEAR1

Sushi, von Willebrand factor type A, EGF and pentraxin domain containing 1 (SVEP1) is an extracellular matrix protein that causally promotes vascular disease and associates with platelet reactivity in humans. Here, using a human genomic and proteomic approach, we identify a high affinity, disease-relevant, and potentially targetable interaction between SVEP1 and the orphan receptor Platelet and Endothelial Aggregation Receptor 1 (PEAR1). This interaction promotes PEAR1 phosphorylation and disease associated AKT/mTOR signaling in vascular cells and platelets. Mice lacking SVEP1 have reduced platelet activation, and exogenous SVEP1 induces PEAR1-dependent activation of platelets. SVEP1 and PEAR1 causally and concordantly relate to platelet phenotypes and cardiovascular disease in humans, as determined by Mendelian Randomization. Targeting this receptor-ligand interaction may be a viable therapeutic strategy to treat or prevent cardiovascular and thrombotic disease. SVEP1 is linked to numerous human diseases, though its disease-promoting mechanism has remained unclear. Here, the authors identify SVEP1 as a ligand for the orphan receptor PEAR1 and provide insight into the role of this interaction in cardiovascular disease.

Automated summary

The study identifies a high affinity interaction between SVEP1 and the orphan receptor PEAR1, which promotes phosphorylation of PEAR1 and activation of AKT/mTOR signaling in vascular cells and platelets. Mice lacking SVEP1 exhibit reduced platelet activation, while exogenous SVEP1 induces PEAR1-dependent activation of platelets. Targeting this receptor-ligand interaction may offer a potential therapeutic strategy for cardiovascular and thrombotic diseases.