SVEP1 is an endogenous ligand for the orphan receptor PEAR1
Jared S. Elenbaas, Upasana Pudupakkam, Katrina Ashworth, Chul Joo Kang, Ved Patel, Katherine Santana, In‐Hyuk Jung, Paul C. Lee, Kendall H. Burks, Junedh Amrute, Robert P. Mecham, Carmen M. Halabi, Arturo Alisio, Jorge Di Paola, Nathan O. Stitziel
Abstract
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.