In summary, the development of atherosclerotic plaques in arteries is influenced by the type of blood flow in the vessel. Using a mouse model that imposes a specific flow pattern in carotid arteries, it has been demonstrated that an
oscillatory shear stress promotes the formation of stable plaques, and that a low laminar shear stress induces the formation of unstable plaques. In contrast, high laminar shear stress does not induce atherosclerosis as it up-‐regulates anti-‐
inflammatory genes in ECs. The Krüppel like transcription factors KLF2 and KLF4 have been identified as central regulators of physiological (anti-‐
inflammatory) responses to HLSS. Cx40 has anti-‐atherogenic properties.
Moreover, these proteins are highly expressed in the endothelium of healthy arteries, but are down-‐regulated in the ECs overlying atheromas.
In this thesis, I will aim to elucidate relationship between different shear stress conditions and the regulation of endothelial Cx40 within the context of atherosclerosis.
More specifically I will:
-‐ investigate the relation between OSS, Cx40 expression and the NF-‐
κB/IκBα-‐complex.
-‐ identify the transcription factor inducing Cx40 expression in HLSS conditions
-‐ identify the downstream consequences of HLSS-‐induced Cx40 expression -‐ investigate whether the zebrafish (Danio rerio) Cx40 orthologues, i.e.
Cx41.8 and Cx45.6, are expressed in the endothelium and what may be the consequences of mutations in these genes to vascular (patho)physiology.
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Jean-‐François Denis1,*, K.E. Ludwig Scheckenbach1,*, Anna Pfenniger1,2, Merlijn J.
Jean-‐François Denis1,*, K.E. Ludwig Scheckenbach1,*, Anna Pfenniger1,2, Merlijn J.