Vascular Calcification

Abstract

Once thought to result from passive precipitation of calcium and phosphate, it now appears that vascular calcification is a consequence of tightly regulated processes that culminate in organized extracellular matrix deposition by osteoblast-like cells. These cells may be derived from stem cells (circulating or within the vessel wall) or differentiation of existing cells, such as smooth muscle cells (SMCs) or pericytes. Several factors induce this transition, including bone morphogenetic proteins, oxidant stress, high phosphate levels, parathyroid hormone fragments, and vitamin D. Once the osteogenic phenotype is induced, cells gain a distinctive molecular fingerprint, marked by the transcription factor core binding factor alpha1. Alternatively, loss of inhibitors of mineralization, such as matrix gamma-carboxyglutamic acid Gla protein, fetuin, and osteopontin, also contribute to vascular calcification. The normal balance between promotion and inhibition of calcification becomes dysregulated in chronic kidney disease, diabetes mellitus, atherosclerosis, and as a consequence of aging. Once the physiological determinants of calcification are perturbed, calcification may occur at several sites in the cardiovascular system, including the intima and media of vessels and cardiac valves. Here, calcification may occur through overlapping yet distinct molecular mechanisms, each with different clinical ramifications. A variety of imaging techniques are available to visualize vascular calcification, including fluoroscopy, echocardiography, intravascular ultrasound, and electron beam computed tomography. These imaging modalities vary in sensitivity and specificity, as well as clinical application. Through greater understanding of both the mechanism and clinical consequences of vascular calcification, future therapeutic strategies may be more effectively designed and applied.

Atherosclerotic Calcification: Wnt Is the Hint

“…VC is a marker for atherosclerosis and is associated with several cardiovascular pathological features, including hypertension, congestive heart failure, cardiac hypertrophy, and ischemia, and increased risk of MI and stroke 38, 39. VC is a significant risk factor for morbidity and mortality in cardiovascular disease 7, 19, 37, 40, 41, 42, 43, 44.…”

“…More recently, evidence is emerging for the role of Wnt signaling in atherosclerosis and, in particular, VC (summarized in Figure 3). 4 Behind the skeleton, the arterial vasculature is the second most extensively calcified structure in the human body 39. Recent evidence demonstrates that Wnt ligands and their receptors play a role in calcification itself as well as the atherosclerotic events that predispose vessels to this pathological calcification.…”

Calcification of the internal elastic lamina of coronary arteries

“…25 Osteoporosis, hyperparathyroidism, elevated calcium phosphate product, chronic renal failure, and diabetes mellitus have all been associated with medial as well as intimal calcification. 2,22,27,28 Although we have little evidence of patients in this study suffering from these conditions, many were HIV-infected and heavily exposed to HAART. It is possible that untested, subclinical, or unknown metabolic disorders among the HIV-positive patients made them susceptible to damage and/or calcification of the internal elastic lamina at a younger age than HIV-negative controls.…”

“…Normally, a balance exists between promoters and inhibitors of calcification, but in chronic renal dysfunction, diabetes mellitus, atherosclerosis, and osteoporosis, as well as aging, a dysregulation of calcification can occur. 22 Each of these metabolic abnormalities is well documented in HIV-positive patients and may be due to HIV infection or to treatment with drugs such as protease inhibitors as part of highly active antiretroviral therapy (HAART). [23][24][25] In a recent meta-analysis, 15% of HIV-infected patients had osteoporosis, for a pooled odds ratio of 3.7 compared to HIV-negative controls.…”

“…Some argue that calcification of an intimal plaque predisposes it to rupture; others believe that calcification increases plaque stability. 22 For many years, Mö nckeberg's sclerosis was considered a completely benign condition; 17,29 now it is thought to lead to increased pulse pressure, left ventricular hypertrophy, peripheral vascular disease, and altered coronary perfusion. 3,28,30 Increasing amounts of calcification detected by computed tomography (CT) predict the likelihood of future coronary events.…”