Smooth Muscle Cell–Specific Expression of Cyclic Nucleotide Phosphodiesterase 10a Promotes the Development of Medial Artery Calcification

BACKGROUND: Medial artery calcification is highly prevalent in patients with CKD and peripheral artery disease. It is strongly associated with higher cardiovascular morbidity and mortality. The second messengers cyclic nucleotides cAMP and cGMP play important regulatory roles in a variety of human diseases, which are controlled by distinct phosphodiesterase (PDE) isozymes. PDEs have proven to be highly effective drug targets for the treatment of various conditions. Their function and regulation in medial artery calcification, however, remain unknown. METHODS: To investigate the role of PDE10A in medial artery calcification, we utilized calcified human tibial arteries from peripheral artery disease patients, calcified arteries from in vivo models, and calcifying vascular smooth muscle cells in vitro. Functional studies were conducted using PDE10A knockdown, overexpression, global deletion, and smooth muscle cell-specific deficiency models. Furthermore, we employed an ex vivo aortic ring culture model. The therapeutic potential of the pharmacological PDE10A inhibitor, TAK-063, was evaluated in two distinct in vivo calcification models: vitamin D3 injection and the 5/6 nephrectomy CKD model. RESULTS: We observed that PDE10A was increased in calcifying vascular smooth muscle cells in vitro, calcified arteries in vivo, and calcified human tibial arteries. Knockdown and inhibition of PDE10A markedly attenuated phosphate-induced smooth muscle cell osteogenic transformation and calcification, whereas overexpression of PDE10A enhanced smooth muscle cell calcification. Consistently, both global and smooth muscle cell-specific PDE10A deficiency significantly reduced medial artery calcification in vivo, and deletion of PDE10A alleviated calcification in the aortic ring model. Mechanistically, PDE10A promoted medial artery calcification through activation of the p38 MAPK-MMP-3 signaling axis. Additionally, the inhibitor TAK-063 significantly reduced medial artery calcification in both the vitamin D3 and 5/6 nephrectomy models. CONCLUSIONS: PDE10A was a critical mediator of medial artery calcification, and pharmacological inhibition effectively reduced medial artery calcification in vivo.