Vascular pathology of medial arterial calcifications in NT5E deficiency: implications for the role of adenosine in pseudoxanthoma elasticum

Abstract

Arterial Calcification due to Deficiency of CD73 (ACDC) results from mutations in the NT5E gene encoding the 5' exonucleotidase, CD73. We now describe the third familial case of ACDC, including radiological and histopathological details of the arterial calcifications. The medial lesions involve the entire circumference of the elastic lamina, in contrast to the intimal plaque-like disease of atherosclerosis. The demonstration of broken and fragmented elastic fibers leading to generalized vascular calcification suggests an analogy to pseudoxanthoma elasticum (PXE), which exhibits similar histopathology. Classical PXE is caused by deficiency of ABCC6, a C type ABC transporter whose ligand is unknown. Other C type ABC proteins transport nucleotides, so the newly described role of adenosine in inhibiting vascular calcification, along with the similarity of ACDC and PXE with respect to vascular pathology, suggests that adenosine may be the ligand for ABCC6.

Fig. 1

Skeletal radiographs of patient. A. Plain radiograph showing calcification of the femoral artery. B. Calcification of the popliteal and posterior tibial arteries. C. Calcification of the internal carotid artery (arrow). D. Calcification in the metacarpal phalangeal joints (arrows).

Fig. 2

Non-contrast CT for valuation of total body calcium. The arteries of the lower extremities display severe calcification and arteriomegaly.

Fig. 3

Alkaline phosphatase staining of control and ACDC (CD73-deficient) fibroblasts. A. Dishes of confluent fibroblasts from a control and the ACDC patient, stained for alkaline phosphatase. No treatment (top); osteogenic medium (bottom). B. Microscopic view of cells shown in A. C. Quantification of alkaline phosphatase enzyme activity, expressed as nM p-nitrophenol produced per μg of fibroblast protein. D. Gene expression of collagen Iα1 in control and ACDC fibroblasts.

Fig. 4

Circumferential views of resected right femoral artery, showing substantial thickening of the media with connective tissue and disrupted elastic fibers. A. Hematoxylin and eosin stain. B. Masson's trichrome stain, showing connective tissue. C. Verhoeff's technique of the Van Gieson reagent stain of elastic fibers.

Fig. 5

Internal elastic lamina of patient's artery (hematoxylin & eosin). A. Tortuous path of elastic lamina (arrowheads) contiguous with calcified outgrowths (arrows). B. Larger calcification (arrow) within the path of the internal elastic lamina. C. Fragmented calcifications (arrow) contiguous with elastic fibers.

Fig. 6

Calcified regions of the patient's vascular wall (hematoxylin & eosin). A. Numerous calcifications (arrows) lining the inner wall of the femoral artery, with remnants of elastic lamina. Inset: Enlarged calcification, showing inhomogeneous collection of material. B. Larger calcified area of vessel. Inset: Extensive calcium deposition with tissue breakdown.

Fig. 7

A model of the purinergic pathway in vascular cells. ATP is converted to pyrophosphate and AMP by ENPP1. CD73 converts AMP to inorganic phosphate and adenosine, which binds to plasma membrane receptors that induce intracellular signaling. This lowers tissue neutral alkaline phosphatase (TNAP), an extracellular, membrane-bound protein. In the absence of TNAP, extracellular pyrophosphate levels increase, inhibiting mineralization.