Genetic pathways of vascular calcification

Abstract

Vascular calcification is an independent risk factor for cardiovascular disease. Arterial calcification of the aorta and coronary, carotid, and peripheral arteries becomes more prevalent with age. Genome-wide association studies have identified regions of the genome linked to vascular calcification, and these same regions are linked to myocardial infarction risk. The 9p21 region linked to vascular disease and inflammation also associates with vascular calcification. In addition to these common variants, rare genetic defects can serve as primary triggers of accelerated and premature calcification. Infancy-associated calcific disorders are caused by loss-of-function mutations in ENPP1, an enzyme that produces extracellular pyrophosphate. Adult-onset vascular calcification is linked to mutations in NTE5, another enzyme that regulates extracellular phosphate metabolism. Common conditions that secondarily enhance vascular calcification include atherosclerosis, metabolic dysfunction, diabetes, and impaired renal clearance. Oxidative stress and vascular inflammation, along with biophysical properties, converge with these predisposing factors to promote soft tissue mineralization. Vascular calcification is accompanied by an osteogenic profile, and this osteogenic conversion is seen within the vascular smooth muscle as well as the matrix. Here, we review the genetic causes of medial calcification in the smooth muscle layer, focusing on recent discoveries of gene mutations that regulate extracellular matrix phosphate production and the role of S100 proteins as promoters of vascular calcification.

Figure 1

Smooth muscle cells contribute to ectopic calcification. Vascular calcification within the medial wall limits vessel extensibility and is associated with increased cardiovascular events. In bone, calcification initiates through matrix vesicles that extrude from cells. Vascular smooth muscle cells (VSMCs, pink) also form matrix vesicles.

Figure 2

Calcified vessels in a female mummy, estimated age 40-45 years old, a princess living in the 17^th Dynasty (1580 to 1550 BCE) of the Second Intermediate Period. Extensive calcification of the aortic and coronary vessels was detected using CT scanning. Reproduced from the Horus Study as published in JACC Cardiovascular Imaging with permission from Elsevier (Allam et al. 2011).

Figure 3

Mutations that disrupt ENNP1 and NT5E cause inherited forms of infantile and adult onset vascular calcification, respectively. ENNP1 encodes NPP1, which hydrolyzes extracellular ATP to generate pyrophosphate (PP_i), an inhibitor of hydroxyapatite formation and calcification. NT5E catalyzes the production of inorganic phosphate (P_i), an accelerator of mineralization. Tissue neutral alkaline phosphatase (TNAP) also generates inorganic phosphate. An imbalance of PP_i, inorganic phosphate and calcium occurs in inherited vascular calcification. Mutations in ABCC6, a gene encoding a nucleotide sensitive transporter, have also been linked to inherited calcification in the form of infantile calcification and pseudoxanthoma elasticum.

Figure 4

Advanced remodeling with calcification, necrotic core and elastic fiber degradation of atherosclerotic plaques in ApoE null mice that express human S100A12 in the smooth muscle (a-c) compared to WT/ApoE littermate mice (d-f). Alizarin Red stain for calcium (a,d), H&E stain (b,e) and Verhoeff van Giessen (VVG) stain for elastic fibers (c,f). L-lumen, FFN-fibrofatty nodule, *** osteoblast like cells. S100A12 is expressed in human smooth muscle atherosclerotic aorta (Image from (Hofmann Bowman et al. 2011)).