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Endothelial disease mechanisms involved in calcific aortic valve stenosis and aortic aneurysm formation in mice and men

The endothelium lines all vessels in our body and plays a critical role in providing all organs with oxygen, metabolites and other factors. The vascular bed and the respective endothelial cell (EC) layer display prominent regional structural and functional specialization in order to fulfill the physiological requirements of the various organs and compartments. This heterogeneity of the endothelium is claimed to have developmental and acquired origins. However, recent evidence suggests that even the endothelium within the same organ can display prominent heterogeneity and that this could be also of pathophysiological relevance. Aortic aneurysm (AA) and aortic valve stenosis (AS) are frequent diseases of the elderly and there are currently no curative treatment options. Importantly, the molecular mechanisms underlying onset and development of these diseases are still unclear. Besides the traditional view that these pathologies are mere degenerative processes due to mechanical stress, recent evidence implies that the endothelium and chronic inflammatory processes play an important role in disease development and progression.

We hypothesize that the molecular heterogeneity of the endothelium defines location, onset and progression of AA and AS and that its in depth analysis will pinpoint molecules, factors and pathways, which are involved in the pathophysiology of these diseases.

In addition, these analyses could lead to the identification of interesting therapeutic targets. Experimentally we will address this important question by exploring differential gene expression via RNA-seq analysis in ECs from thoracic and abdominal segments of aortas from healthy and diseased mice with AA (Aim 1). Similarly, this type of analysis will be performed on human control and stenotic aortic valves (Aim 2). The molecular and functional role of genes of interest will be explored in ECs in vitro and in vivo using overexpression or knock-out strategies. We will also examine the role of ecto-5-nucleotidase (CD73)+ cells and mesenchymal stem cells (MSCs) in AA and AS formation and in progression as well as calcification and inflammation and their impact on the EC layer using a CD73/eGFP in vivo model (Aim 3). Taken together, our project aims at elucidating the role of the heterogeneity of the endothelium in AA and AS onset and progression and identifying new therapeutically relevant targets.



B01 Hypothesis: Regional heterogeneity of aortic endothelium dictates disease development through distinct susceptibility of stressors such as mechanical strain and through interaction with circulating non-resident and resident cells.

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