Abstract

The Role of Exosomes in Vascular Calcification

Alexander Kapustin, Research Associate, King's College London

Vascular calcification is a ubiquitous pathology in the aged and diseased vasculature and is associated with increased mortality and morbidity. Calcification was once considered to be due to passive degenerative processes, however accumulating evidence suggests that calcification is driven by cell-mediated processes similar to bone formation. Vascular smooth muscle cells (VSMCs) uniquely orchestrate the calcification process a number of processes are required for calcification to occur. These include loss of expression/function of local (Matrix Gla protein (MGP)) and circulating (fetuin-A) inhibitors of calcification, the induction of osteo/chondrocytic differentiation of VSMCs, which is characterized by upregulation of a number of mineralization-regulating proteins and ECM components normally expressed in bone, as well as apoptosis and the release of membrane bound vesicles which form the first nidus for mineralization. Recently we have focused on the earliest events in the calcification process and have shown that calcification is initiated in small membrane-bound bodies, or matrix vesicles, derived from both apoptotic and stressed VSMCs. 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 proteins are lacking or dysfunctional, or vesicle release is overwhelming calcification ensues. More recent work has focussed on the mechanisms via which matrix vesicles calcify and we have identified annexins and phosphatidyl serine as important in forming a nucleation complex for the initiation of mineralization. We have also made progress in identifying the sub-cellular origin of VSMC-derived matrix vesicles and have identified them as exosomes, which are released in response to a number of factors in an SMPD3 dependent-manner. Importantly blocking exosome release can ameliorate VSMC calcification. Our work i