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.

Background: Sushi, von Willebrand factor type A, EGF and pentraxin domain containing 1 (SVEP1) is an extracellular matrix protein that circulates in plasma and is causally related to cardiovascular disease, hypertension, and type 2 diabetes. A recent genome wide association study (GWAS) also implicates SVEP1 in platelet reactivity. The gene most strongly associated with platelet reactivity in the GWAS is Platelet and Endothelial Cell Receptor 1 ( PEAR1 ), a gene that encodes an orphan receptor tyrosine kinase-like protein that also associates with cardiovascular disease. Little is known about the molecular interactions and disease mechanisms of these proteins, despite their associations with cardiovascular disease and platelet reactivity. Methods: We used Mendelian Randomization (MR) and phenome-wide association studies to identify candidate SVEP1 protein interactions. We tested candidate interactions using recombinant proteins with molecular, cellular, and ex vivo assays. Results: A coding variant within the ectodomain of PEAR1 alters plasma levels of SVEP1 in humans (p=1.7x10^-17), suggesting these proteins may interact. MR demonstrates that genetically determined, increased plasma PEAR1 levels causally associate with decreased plasma SVEP1 (p=1.3x10^-11), further supporting an interaction. PEAR1 co-immunoprecipitates with SVEP1. Exposure to SVEP1 induces PEAR1 phosphorylation and activation of AKT/mTOR signaling in endothelial cells, vascular smooth muscle cells, and platelets. siRNA knockdown of PEAR1 abrogates this signaling. Endothelial cells adhere and proliferate in response to immobilized SVEP1. Platelets isolated from mice lacking SVEP1 have lower activation relative to controls and phenocopy platelets from mice lacking PEAR1. Conclusions: Despite robust evidence for the role of SVEP1 and PEAR1 in cardiovascular disease, critical gaps remain in our understanding of their disease mechanisms. Here, we identify SVEP1 as the first biological ligand of PEAR1 and a potent activator of AKT/mTOR signaling. The interaction between SVEP1 and PEAR1 is particularly intriguing, given the prominent role of AKT/mTOR in cardiovascular disease, and disrupting the interaction may be therapeutically beneficial.

In this article the author name Arturo Alisio was incorrectly written as Arturo Aliso. The original article has been corrected.