Regulation of vasoactive peptides by cardiovascular risk factors was investigated in the first part of this study. The main focus was on the investigation of interactions between the renin angiotensin system and the endothelin system. In animal models of cardiovascular risk factors (aging, obesity, excessive erythrocytosis) and in retrospective studies using myocardium of patients with heart failure indications of an activation of the endothelin system and the renin angiotensin system were found. Pharmacological inhibition of components of the renin angiotensin system or the endothelin system modulates these effects. In contrast, there was no evidence for a direct impact of angiotensin II on the endothelin system in primary human endothelial cells. Different flow conditions with varying shear stress are thought to be involved in the localisation of atherosclerotic plaques in the vasculature. Whether mediators of vascular development play a role in these structural changes of the vessel wall in the area of atheroma has not been investigated so far. Therefore, in the second part of this study the regulation of mediators of vascular development (ephrin-B2, EphB4, angiopoietin-2, Tie2) by mechanical forces (shear stress) was investigated in human endothelial cells. High laminar shear stress (30 dyne/cm², 24 h) mediates a downregulation of ephrin-B2 and angiopoietin-2 expression. In contrast, low shear stress (1 dyne/cm², 24 h) induces angiopoietin-2 expression. Downregulation of ephrin-B2 is extracellular matrix-dependent. Inhibition of protein kinase C prevents downregulation of ephrin-B2 and angiopoietin-2. These data support a vasoprotective potential of augmented laminar shear stress via stabilisation of the vasculature. |