Acute cardiovascular syndromes (ACS) are the main cause of death in Western society and are caused by atherosclerosis. Intraplaque hemorrhage is a key characteristic of an unstable atherosclerotic plaque at risk for rupture. We propose here that therapeutic approaches to prevent the incidence of intraplaque hemorrhage is a powerful strategy to limit the incidence of ACS and reduce overall disease burden. 
Intraplaque hemorrhage is caused by leakage of intraplaque microvessels. We hypothesize that mast cells, a potent immune cell type, induce microvascular instability in advanced atherosclerosis and is causally involved in the incidence of intraplaque hemorrhage. 
We aim to a) elucidate how mast cells in atherosclerosis contribute to microvessel instability and hemorrhage and b) develop therapeutic strategies inhibiting mast cell induced vascular leakage to prevent intraplaque hemorrhage and subsequent ACS.
To address these aims, we envision the following strategy:
1) Identify atherosclerosis specific mast cell phenotypes and druggable targets using human atherosclerotic plaque cells.
2) Fate mapping of mast cells in atherosclerosis: to understand the underlying processes of mast cell accumulation in atherosclerosis, we will assess the origin of the mast cells in the plaque. 
3) Characterize mast cell dependent intraplaque angiogenesis and hemorrhage: to establish a causal role between mast cells, atherosclerosis, intraplaque angiogenesis and hemorrhage, we will perform mast cell activation and inhibition studies will be performed in apoE-/-Fbn1C1039G+/-, a unique mouse model that presents all these features. 
4) Provide therapeutic strategies to prevent plaque instability using human ex vivo atherosclerosis models and experimental models of advanced atherosclerosis.
Together, we will gain novel insights in mast cell-induced intraplaque hemorrhage, and novel therapeutic intervention strategies to improve plaque stability and to limit the incidence of ACS.