Fig. 6. The two roles of ENPP1: inhibiting arterial calcification and myointimal proliferation by modulating extracellular PP_i and ATP metabolism.

The transmembrane ectoenzyme ENPP1 converts extracellular ATP to AMP and thereby generates PP_i. AMP is further hydrolyzed by CD73 (5-exonucleotidase) to adenosine and P_i. PP_i is a physiologic inhibitor of hydroxyapatite formation, regulates chondrogenesis and is therefore important in the prevention of soft tissue calcification. A decreased PP_i/P_i ratio leads to calcification. Elevated extracellular ATP levels lead to increased VSMC proliferation, while AMP and adenosine are known to inhibit VSMC proliferation. In ENPP1 deficiency, independent of low PP_i levels, proproliferating extracellular ATP levels increase, whereas antiproliferating AMP and adenosine levels decrease, leading to accelerated VSMC proliferation and arterial stenosis. We conclude that a decreased PP_i/P_i ratio leads to ectopic calcification, whereas an increased extracellular ATP/AMP ratio leads to increased VSMC proliferation and arterial stenosis in ENPP1 deficiency