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. 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.

Urokinase Receptor Mediates Osteogenic Differentiation of Mesenchymal Stem Cells and Vascular Calcification via the Complement C5a Receptor

“…Consequently, no effective therapies are available. Increasing body of recent evidence has challenged the traditional consideration of vascular calcification as a passive aging-related process and points to specific mechanisms of its regulation depending on diseaserelated environmental cues [32,33]. A role of circulating calcifying cells in this process is emerging [34].…”

Serum myostatin levels are negatively associated with abdominal aortic calcification in older men: the STRAMBO study

“…Mineralization of the vasculature is associated with an excess risk of cardiovascular events due to an increase in arterial stiffness and pulse wave velocity (32,33). Different factors including a mineral imbalance promote vascular calcification, whereas endogenous local or circulating calcification inhibitors suppress vascular calcification by blocking the deposition of minerals in the vascular wall or by the transformation of vascular smooth muscle cells (VSMC) to osteochondrogenic cells (34).…”

Runx2 deletion in smooth muscle cells inhibits vascular osteochondrogenesis and calcification but not atherosclerotic lesion formation

“…8 Although initially considered a passive, uncontrollable process, recent evidence supports AIC as an actively regulated process with similarities to bone development, including the appearance of calcified cartilage-and bone-like structures within le-sions. [9][10][11] Lineage tracing studies in mouse models have shown that vascular smooth muscle cells (SMCs) can transdifferentiate into osteochondrogenic cells, 12,13 implicating these cells as important mediators of AIC. However, the mechanisms by which SMCs transdifferentiate and contribute to plaque mineralization are not well understood.…”