The primary focus of Ann's reserach is to elucidate the molecular and cellular mechanisms regulating pathological vascular calcification, which is highly correlated with increased morbidity and mortality in patents with atherosclerosis, diabetes and end-stage renal disease. Her group was the first to demonstrate that vascular pericytes may be involved in this process as she demonstrated that these cells can differentiate along several lineages including osteogenic, chondrogenic and adipogenic in response to specific stimuli. She has now confirmed that vascular smooth muscle cells (VSMC) can also undergo osteogenic differentiation and deposit a mineralised matrix. Using both pericytes and vascular smooth muscle cells, she has demonstrated that the Wnt- and TGFbeta-signaling pathways are master controllers of differentiation and that they also contribute to the pathogenesis of vascular calcification. In addition, she has discovered other novel inhibitors of vascular calcification including TSG-6, CaR, Axl and its ligand, Gas6 and HtrA1 (a serine protease with the ability to regulate TGFbeta signalling). Therefore, current research aims to determine the mechanisms by which these signaling pathways regulate pericyte and VSMC differentiation and vascular calcification. Ultimately, these studies should enable us to develop approaches to (a) prevent pathological calcification, and (b) manipulate cells along VSMC lineages for therapeutic tissue regeneration.
Molecular and Cellular mechanisms underpinning Vascular Calcification
Vascular calcification is a common complication of many diseases including atherosclerosis, diabetes, renal disease, hypertension, vein graft failure and calciphylaxis. Recent studies have shown that there is a strong association between the presence of vascular calcification and adverse clinical events such as myocardial infarction and stroke. However, little is known about how the deposition of mineral in vessels is controlled. We have shown that vascular pericytes have multi-lineage potential and can differentiate into osteoblasts and chondrocytes in vitro and in vivo. We have also shown that these cells can deposit a calcified matrix resembling that found in calcified atherosclerotic plaques, suggesting that pericytes may mediate, at least in part, vascular calcification. We have recently demonstrated that several genes that are implicated in the pathological calcification of arteries, namely matrix Gla protein, Axl receptor tyrosine kinase and HtrA1 serine protease are all differentially expressed during pericyte differentiation. We are currently using molecular, cellular and biochemical approaches to elucidate the mechanisms by which each of these proteins regulates calcification. In time, this integrated programme of research will provide important insights into the pathogenesis of vascular calcification and may identify potential targets for the therapeutic manipulation of this event.