Cellular signaling events in the pathogenesis of arterial stiffening: an approach to identify Cbfa1 (core binding factor alpha1) as a key mediator of vascular remodeling

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Arterial stiffening is associated with ageing and numerous disease states such as hypertension, congestive heart failure, diabetes mellitus or renal failure. Here arterial stiffness may represent a central pathophysiologic factor that alters/impairs macro- and microcirculation resulting in disease progression. In accordance increased arterial stiffness has been identified as an independent risk factor for cardiovascular disease. Consequently modulation of arterial stiffness represents an attractive therapeutic target for a plenty of diseases. However, effective therapies that target the structural abnormalities and changes in vascular signaling that underlie the process of stiffening are currently lacking.Vascular remodeling (i.e. the structural correlate of arterial stiffening) comes along with an altered pattern of gene expression and activation of specific cellular signaling pathways. Preliminary data indicate a critical role of the transcription factor, core binding factor alpha1 (Cbfa1) as a mediator of arterial stiffening.This project is based on the assumption that Cbfa1 is a universal regulator of vascular fibrosis and arterial stiffening. The aim of this project therefore is to test the hypotheses that 1) arterial Cbfa1 expression is commonly induced by diverse triggers of vascular stiffening (e.g., mechanical stress, hormones as angiotensin II or insulin, glucose, etc.), 2) enhanced Cbfa1 activity, per se, results in increased vascular stiffness and finally 3) Cbfa1 is a critical mediator in differentially induced processes of arterial stiffening. In a more general approach apart from Cbfa1 expression 4) further universal signaling events in arterial stiffness shall be identified.The results of the present project elucidate a novel mechanism that may underlie arterial stiffening (Cbfa1 signaling; hypotheses 1-3) and moreover may identify further potential targets for therapeutic intervention (hypothesis 4).