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A low-frequency variant of sushi, von Willebrand factor type A, EGF and pentraxin domain containing protein 1 (SVEP1), an extracellular matrix protein, is associated with risk of coronary disease in humans independent of plasma lipids. Despite a robust statistical association, if and how SVEP1 might contribute to atherosclerosis remained unclear. Here, using Mendelian randomization and complementary mouse models, we provide evidence that SVEP1 promotes atherosclerosis in humans and mice and is expressed by vascular smooth muscle cells (VSMCs) within the atherosclerotic plaque. VSMCs also interact with SVEP1, causing proliferation and dysregulation of key differentiation pathways, including integrin and Notch signaling. Fibroblast growth factor receptor transcription increases in VSMCs interacting with SVEP1, and is further increased by the coronary disease-associated SVEP1 variant p.D2702G. These effects ultimately drive inflammation and promote atherosclerosis. Taken together, our results suggest that VSMC-derived SVEP1 is a pro-atherogenic factor, and support the concept that pharmacological inhibition of SVEP1 should protect against atherosclerosis in humans.

SummaryA low-frequency variant of SVEP1, an extracellular matrix protein, is associated with risk of coronary disease in humans independent of plasma lipids. Despite a robust statistical association, however, it was unclear if and how SVEP1 might contribute to atherosclerosis. Here, using Mendelian randomization and complementary mouse models, we provide evidence that SVEP1 promotes atherosclerosis in humans and mice. We find that SVEP1 is expressed by vascular smooth muscle cells (VSMCs) within the atherosclerotic plaque. VSMCs also interact with SVEP1, causing proliferation and dysregulation of key differentiation pathways, including integrin and Notch signaling. Fibroblast growth factor receptor transcription increases in VSMCs interacting with SVEP1, and is further increased by the coronary disease-associated SVEP1 variant. These effects ultimately drive inflammation and promote atherosclerosis. Taken together, our results suggest that VSMC-derived SVEP1 is a pro-atherogenic factor, and support the concept that pharmacological inhibition of SVEP1 should protect against atherosclerosis in humans.