The team’s main goal is to identify mechanisms and entities which regulate adult vessel wall smooth muscle cell (VSMC) phenotype change, a process contributing to the pathogenesis of numerous cardiovascular disorders. Phenotypic changes in VSMC biology, in the context of arterial tissue-specific spatio-temporal physiology and structure, are important determinants of the evolution of atherothrombotic and non-atherothrombotic pathologies within the arterial wall. Atherosclerosis is the cause of most heart attacks and strokes, and is undoubtedly, an age-related disease. There is growing evidence for a pivotal role of VSMC phenotypic switching in atherosclerosis. Because we have demonstrated that Adenylyl Cyclase (AC) 8 expression is closely linked to the properties developed by VSMC in atherosclerosis and hyperplasia post-angioplasty, one of our 2 projects aims in characterizing the functional role of AC8 in pathological vascular remodelling as well as the impact of aging on AC8-regulated VSMC function; it will also specify the AC8-induced signaling pathways involved in trans-differentiated VSMC responses including the effect of AC8 over-expression on cAMP/EPAC signal integration using FRET biosensors imaging. Taking advantage of our background, we expanded our projects and started deciphering mechanisms which possibly disrupt cerebro-vascular integrity in the aged brain. Such disruption to cerebro-vascular integrity is a major risk factor for Alzheimer's disease and vascular dementia. Regarding the importance of inflammation in vascular alterations, we will further investigate cell type specific contribution to- and the molecular mechanisms underlying- the inflammatory context generated by ?-amyloid accumulation in vessel walls. We plan to establish miRNA profiling of ?-amyloid-treated endothelial and smooth muscle cells for a better understanding of the early events of the disease progression. We should also characterize in vivo the potential beneficial effect of the truncated form of thioredoxin, Trx-80, on the ontogenesis of cerebrovascular amyloid angiopathy and Alzheimer disease. The rationale for such a project relies on several observations demonstrating that Trx-80 inhibits amyloid-? aggregation. These studies bring the Unit’s investigation to the interface between fundamental molecular biology, neuroscience and cardiovascular pathophysiology and the effect of age thereon. | |