The vascular biology of calcification.

Vascular calcification is an active, cell-mediated process that results from an imbalance between the promoters and inhibitors of mineralization. The process of vascular calcification shares many similarities with that of skeletal mineralization. However, while skeletal mineralization is a regulated process induced by complex, well-timed developmental cues, vascular calcification is a pathological process, occurring in response to dysregulated/inappropriate environmental cues. Damage inducing agents present in the uremic milieu such as a mineral imbalance, induce vascular smooth muscle cell (VSMC) apoptosis, and vesicle release resulting in mineral nucleation and the deposition of hydroxyapatite. Under normal conditions, inhibitors of soft-tissue mineralization such as matrix gamma-carboxyglutamic acid protein are expressed locally within the vessel wall while others such as fetuin-A are present in the circulation. Down-regulation or perturbation of these proteins leads to a phenotypic transformation of VSMC into osteo/chondrocytic-like cells that have the capacity to modulate the mineralization process. Many aspects of the mechanisms underlying vascular calcification have been defined through in vitro studies and molecular biological techniques; however, there are still unanswered questions, particularly with respect to the relationship between bone and vascular calcification, processes that appear to be inversely related. A better understanding of the complex mechanisms regulating tissue calcification may have therapeutic potential in reducing the cardiovascular disease-associated morbidity and mortality in patients with renal disease.