Chronic Angiotensin II Augments Integrin-Dependent Cell Functions Via PKC and Map-Kinase Activation in Rat Vsmcs
The activation of local and systemic renin-angiotensin-system is directly and indirectly involved in the mechanisms of vascular remodeling during chronic hypertension. The following study investigated the effect of chronic angiotensin II (AII) admininstration on cell- matrix interaction of VSMCs in vitro. Adhesion to vitronectin (VN) and collagen I (ColI) as well as migration of rat vascular smooth muscle cells (VSMCs) were significantly augmented by chronic treatment with AII for 48 hours and 72 hours. These changes were not due to an increase of the integrins on the cells surface known to be capable in binding vitronectin and collagen I: alpha1, alpha5, beta1 and beta5, as demonstrated by flow cytometry. Also the phosporylation of the focal adhesion kinase (FAK), known to play an important role in adhesion and spreading processes, was not affected after chronic stimulation with Ang II. Downregulation of PKC activity by phorbol-myristate acetate (PMA, 0.1μmol/L), or treatment with the PKC inhibitor calphostin C before treatment with AII significantly reduced the effect of AII on adhesion to VN and ColI (each p<0.05) and also inhibited the effect on VSMC migration (p<0.01). Inhibition of MAP-kinase activation with PD 98059 before treatment with AII demonstrated comparable effects. PD 98059 significantly reduced the increase in adhesion on both, VN and ColI and diminished the effect on PDGF-directed migration of rVSMCs. Theses data indicate that regulation of these functional alterations in integrin-dependent cellular behaviour after chronic AII treatment involved protein kinase C (PKC) and mitogen-activated protein kinase (MAPK)-activation. These data demonstrate that Ang II plays a critical role in augmenting cellular functions in VSMCs, which are important molecular events for the development of vascular hyperplasia .