Artery wall calcification associated with atherosclerosis frequently contains fully formed bone tissue including marrow. The cellular origin is not known. In this study, bone morphogenetic protein-2a, a potent factor for osteoblastic differentiation, was found to be expressed in calcified human atherosclerotic plaque. In addition, cells cultured from the aortic wall formed calcified nodules similar to those found in bone cell cultures and expressed bone morphogenetic protein-2a with prolonged culture. The predominant cells in these nodules had immunocytochemical features characteristic of microvascular pericytes that are capable of osteoblastic differentiation. Pericyte-like cells were also found by immunohistochemistry in the intima of bovine and human aorta. These findings suggest that arterial calcification is a regulated process similar to bone formation, possibly mediated by pericyte-like cells. (J. Clin. Invest. 91:1800-1809.)

Abstract

No abstract

M ost individuals aged Ͼ60 years have progressively enlarging deposits of calcium mineral in their major arteries. 1 This vascular calcification reduces aortic and arterial elastance, which impairs cardiovascular hemodynamics, resulting in substantial morbidity and mortality [2][3][4] in the form of hypertension, aortic stenosis, cardiac hypertrophy, myocardial and lower-limb ischemia, congestive heart failure, and compromised structural integrity. [5][6][7] The severity and extent of mineralization reflect atherosclerotic plaque burden 8 and strongly and independently predict cardiovascular morbidity and mortality. 9 Previously considered passive and degenerative, vascular calcification is now recognized as a pathobiological process sharing many features with embryonic bone formation. As evidence of this change in paradigm, research on vascular calcification has accelerated dramatically in the past decade. A search of PubMed (www.ncbi.nlm.nih.gov; US National Library of Medicine) under the key words vascular calcification returned Ϸ16 articles in 1982, 100 in 1994, and 250 in 2004. This year, 400 new publications are expected, for a total Ͼ3500.A breakthrough in this field was the recognition of its similarity to bone development and metabolism, in which endothelial, mesenchymal, and hematopoietic cells interact and respond to mechanical, inflammatory, metabolic, and morphogenetic signals governing skeletal mineralization; their counterparts in the artery wall govern arterial mineralization. With increasing age and dysmetabolic conditions in our population, the clinical burden of vascular calcification will continue to increase. Clinical Impact of Arterial CalcificationAortic calcification promotes congestive heart failure by eroding compliance and elastance. The hemodynamic demands of the cardiovascular system require that the aorta store energy in its elastance during systole and release it during diastole, which minimizes cardiac work and is the basis for balloon counterpulsation. This function, known as Windkessel physiology, is reflected in the high density of elastin in the arch, where mechanical energy is highest. Its loss is detectable as increased arterial pulse wave velocity in calcified arteries, resulting in thoracic summation of reflected and orthograde pressure waves, thereby increasing systolic and pulse pressures. It also increases cardiac work, promoting heart failure, left ventricular hypertrophy, and diastolic dysfunction, independently of atherosclerosis, aging, or diabetes. The link between aortic rigidity and heart failure is most evident in the hypertensive cardiomyopathy observed in patients with idiopathic infantile arterial calcification and in animal models with aortic banding.In the aortic valve, calcification produces life-threatening aortic stenosis. Although previously considered a passive, degenerative, untreatable disorder of "wear and tear" unrelated to atherosclerosis, recent findings now show that valvular calcification is regulated in a manner similar to that of atheroscler...

In the past decade, the prevalence, significance, and regulatory mechanisms of vascular calcification have gained increasing recognition. Over a century ago, pathologists recognized atherosclerotic calcification as a form of extraskeletal ossification. Recent studies are identifying the mechanisms of this remarkable process as a recapitulation of embryonic endochondral ossification through phenotypic plasticity of vascular cells that function as adult mesenchymal stem cells. These embryonic developmental programs, involving bone morphogenetic proteins and potent osteochondrogenic transcription factors, are triggered and modulated by a variety of inflammatory, metabolic, and genetic disorders particularly hyperlipidemia, chronic kidney disease, diabetes, hyperparathyroidism, and osteoporosis. They are also triggered by loss of powerful inhibitors, such as fetuin-A, matrix GLA protein, and pyrophosphate, which ordinarily restrict biomineralization to skeletal bone. Teleologically, soft tissue calcification probably serves to create a wall of bone to sequester noxious foci such as chronic infections, parasites, and foreign bodies. This review focuses on atherosclerotic calcification, with reference to other forms of cardiovascular calcification, such as medial and valvular calcification, each of which warrants its own review. The capacity of the asculature to produce mineral in culture and to produce de novo, vascularized, trabecular bone and cartilage tissue, even in patients with osteoporosis, should intrigue investigators in tissue engineering and regenerative biology.