Regulatory mechanisms in vascular calcification

Abstract

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. Studies are now identifying the mechanism of this remarkable process as a recapitulation of embryonic endochondral and membranous 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 might serve to create a wall of bone to sequester noxious foci such as chronic infections, parasites, and foreign bodies. This Review focuses on atherosclerotic and medial calcification. The capacity of the vasculature 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.

Figure 1

Histological sections of human vascular calcification. Medial arterial calcification, osseous metaplasia, and cartilaginous metaplasia (mineral is stained balck by the von Kossa method and eosin counterstain; original magnification X 40; provided by M. Fishbein, Department of Pathlogy and Laboratory Medicine, University of California, Los Angeles, CA, USA.) (B) Higher-power view of a sequential section from (A) showing chondrocytes in a basophilic matrix (arrows). (C) The tunica media of a human artery (hematoxylin and eosin stain; the lumen contains a thrombus). The yellow arrows indicate amorphous mineral, and the blue arrow identifies a region of osseous tissue that includes a marrow space. (Original magnification X 100; provided by J. H. Qiao, Department of Pathology, California Hospital Medical Center, Los Angeles, CA, USA.)

Figure 2

Chondro-osseous calcific vasculopathy of the medial layer of an atherosclerotic human artery. Histological section (hematoxylin and eosin stain; original magnification X100; provided by Qiao, J.H., Mertens, R. B., Fishbein, M.C. & Geller S.A. Cartilagenous metaplasia in calcified diabetic peripheral vascular disease: morphologic evidence of endochondral ossification. Hum. Pathol. 34(4), 402–407© 2003, with permission from Elsevier).

Figure 3

Regulatory factors in vascular calcification. The Venn diagram illustrates overlap between the three categories of factors regulating vascular calcification. The importance of oxidized lipids (OxL) and hyperphosphatemia is reflected by their inclusion in each category.