Vascular calcification is a ubiquitous pathology in the aged and diseased vasculature occurring at two sites in the vessel wall; in the intima in association with atherosclerosis and in the media in association with ageing, diabetes, and end-stage renal disease. Calcification at either site is associated with adverse cardiovascular outcomes including increased risk of myocardial infarction and arterial stiffness. Numerous studies have observed that vascular calcification and cardiovascular mortality are increased in association with osteoporosis suggesting a possible link between these two processes. Indeed, overwhelming evidence has now established that vascular calcification is an actively regulated, cell-mediated process, similar to bone formation, that is orchestrated by vascular smooth muscle cells (VSMCs). VSMCs modulate to an osteo/chondrocytic phenotype in response to injury, and this is associated with upregulation of the obligate bone/cartilage transcription factors Runx2 and Sox9. VSMCs also release matrix vesicles and these small membrane-bound bodies, derived from both apoptotic and stressed VSMCs are capable of nucleating hydroxyapatite. Under normal conditions, these vesicles are loaded with potent inhibitors of mineralization, including matrix Gla protein (MGP) and fetuin-A, which act to block or control crystal nucleation and growth. However, if these inhibitory proteins are lacking or dysfunctional, or vesicle release is overwhelming calcification ensues. Importantly, a number of key proteins and pathways have been shown to regulate both vascular calcification and bone mineralization. These include osteoprotegerin, bone morphogenetic proteins (BMPs), and inflammatory pathways. Recent data suggests that the DNA damage response may activate a number of these pathways to drive vascular calcification locally and may potentially also induce systemic changes that concomitantly impact on bone homeostasis.
Learning objectives: Vascular calcification is a cell-mediated process with similarities to bone formation.
VSMCs orchestrate vascular calcification.
Calcification involves cell death, loss of inhibitors and osteo/chondrogenic differentiation of VSMCs.
Ageing is a key driver of vascular calcification.
A number of key signaling pathways drive VSMC osteo/chondrogenic differentiation.
Evidence that vascular calcification and bone mineralization are co-regulated.
17 May 2014 - 20 May 2014