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Vascular calcification is highly prevalent in patients with diabetes mellitus and chronic kidney disease. When located in the media, arterial calcification is strongly associated with increased cardiovascular morbidity and mortality. The second messenger cyclic nucleotides cAMP and cGMP, controlled by distinct cyclic nucleotide phosphodiesterase (PDE) isozymes, play important regulatory roles in a variety of human diseases. Using a qPCR PDE array, we found that PDE10A was the most highly induced among all PDE genes in a rat model of medial artery calcification. PDE10A expression was markedly increased in calcified arteries from rats with chronic kidney disease and in tibial arteries from patients with peripheral artery disease. Interestingly, it co-localized with osteogenic markers in these specimens. In vitro , PDE10A knockdown using siRNA, and inhibition with a synthetic inhibitor markedly reduced osteogenic transformation and calcification of vascular SMC exposed to high phosphate levels. Aortic rings from PDE10A knockout mice showed significantly less Pi-induced medial calcification than those from wild-type controls. Deficiency of PDE10A also reduced medial calcification in a mouse medial calcification model in vivo . Mechanistic studies to elucidate the signaling alterations invoked by PDE10A are ongoing. These findings suggest that PDE10A plays a crucial role in the development of medial artery calcification, and that targeting it may provide a novel therapeutic strategy for reducing medial calcification and improving outcomes in patients with PAD.

Objectives: Clinical studies demonstrate associations between arterial calcification and adverse outcomes in patients with peripheral arterial disease. The causal relationship between calcification and ischemia, however, remains unclear. This study aims to evaluate the effects of arterial calcification on functional recovery and limb perfusion following acute limb ischemia in a murine model. Methods: Arterial calcification was induced in 64 Sprague-Dawley rats using Vitamin D 3 . A control group of 32 rats received vehicle only. After 2 weeks, to allow for calcification, unilateral hindlimb ischemia was induced by ligation and excision of the superficial femoral artery. At weekly intervals, functional and ischemia status were evaluated in a blinded manner and laser Doppler perfusion imaging was performed. Results: Calcium assay demonstrated greater arterial calcification in the superficial femoral arteries (0.1 vs. 17.0, P < .01) of Vitamin D 3 injected animals. Rats injected with Vitamin D3 showed significantly worse Tarlov, Ischemia, Modified Ischemia, and Total Ischemia scores at each post-operative time point (Week 1: 16.6 vs. 14.5 P Conclusions: Vitamin D3 induced calcification is associated with decreased perfusion and worse functional recovery in a rat model of hindlimb ischemia. Future research aimed at understanding the relationship between vitamin D 3 , arterial calcification, and lower extremity ischemia may help to improve outcomes in patients with PAD.

Objective— The phenotypic modulation of vascular smooth muscle cells (VSMCs) to a synthetic phenotype is vital during pathological vascular remodeling and the development of various vascular diseases. An increase in type I collagen (collagen I) has been implicated in synthetic VSMCs, and cyclic nucleotide signaling is critical in collagen I regulation. Herein, we investigate the role and underlying mechanism of cyclic nucleotide phosphodiesterase 1 (PDE1) in regulating collagen I in synthetic VSMCs. Methods and Results— The PDE1 inhibitor IC86340 significantly reduced collagen I in human saphenous vein explants undergoing spontaneous remodeling via ex vivo culture. In synthetic VSMCs, high basal levels of intracellular and extracellular collagen I protein were markedly decreased by IC86340. This attenuation was due to diminished protein but not mRNA. Inhibition of lysosome function abolished the effect of IC86340 on collagen I protein expression. PDE1C but not PDE1A is the major isoform responsible for mediating the effects of IC86340. Bicarbonate-sensitive soluble adenylyl cyclase/cAMP signaling was modulated by PDE1C, which is critical in collagen I degradation in VSMCs. Conclusion— These data demonstrate that PDE1C regulates soluble adenylyl cyclase/cAMP signaling and lysosome-mediated collagen I protein degradation, and they suggest that PDE1C plays a critical role in regulating collagen homeostasis during pathological vascular remodeling.