Abstract 5896: Role of the Phosphatase PTEN During Vascular Remodeling
Background: The phosphatase PTEN represents an important physiological inhibitor of phosphatidylinositol-3 kinase (PI3-K)/protein kinase B (Akt) signalling, however, the functional role of PTEN during vascular remodeling remains elusive. In the present study we sought to determine PTEN’s effect on vascular smooth muscle cell (VSMC) function and neointima formation in vivo.
Methods and Results: Immunohistochemistry indicated a faint expression and equal distribution of PTEN in uninjured rat carotid arteries. 12h following balloon-injury, PTEN expression was strongly increased in apoptotic (TUNEL+) VSMC. In vitro, stimulation with serum or different growth factors had no effect on PTEN expression, whereas stimulation with H2O2 robustly increased PTEN expression in a time- and dose-dependent manner. To evaluate the functional role of PTEN expression, human VSMC were transduced with WT-PTEN. Overexpression of PTEN increased the number of apoptotic VSMC (14.8±2.3 vs. 3.6±0.8%, P< 0.05) as determined by TUNEL assay. In contrast, siRNA-mediated knock-down of PTEN attenuated the basal as well as H2O2-induced apoptosis of VSMC. Mechanistically, overexpression of PTEN prevented serum-induced Akt-phosphorylation, whereas siRNA-mediated knock down of PTEN augmented Akt-activation. Moreover, co-transfection of PTEN and a constitutive active Akt mutant prevented VSMC from PTEN-induced apoptosis, indicating, that PTEN regulates VSMC apoptosis by inhibition of Akt phosphorylation/activation.
Conclusion: By interfering with the PI3-K/Akt-dependent survival signalling, the oxidative stress-induced upregulation of PTEN in VSMC of injured arteries augments the sensitivity of VSMC to apoptotic stimuli in the early phase following vascular injury. Thus, these data add substantially to our understanding of PTEN’s role during vascular remodelling.