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Articles in PresS, published online ahead of print March 8, 2002
Am J Physiol Lung Cell Mol Physiol, 10.1152/ajplung.00010.2002
Submitted on January 10, 2002
Accepted on March 3, 2002
1 Medicine, University of Pennsylvania, Philadelphia, PA, USA
2 Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USA
* To whom correspondence should be addressed. E-mail: krymskay{at}mail.med.upenn.edu.
Human vascular smooth muscle cell proliferation and migration contribute to vascular remodeling in pulmonary hypertension and atherosclerosis. The precise mechanisms that regulate structural remodeling of the vessel wall remain unknown. This study tests the hypothesis that PI3K activation is both necessary and sufficient to mediate human PVSM cell proliferation and migration. Microinjection of human PVSM cells with a dominant negative class IA PI3K (p110-DN) inhibited PDGF-induced DNA synthesis by 65% (P<0.001; Chi-square analysis) as compared to cells microinjected with control plasmid, while microinjection of cells with a constitutively active class IA PI3K (p110*-CA) was sufficient to induce DNA synthesis (the mitotic index of p110*-CA-microinjected cells was 15%, compared to 3% in control cells, P<0.01; Chi-square analysis). Transfection of PVSM cells with p110*-CA was also sufficient to promote human PVSM cell migration. In parallel experiments, stimulation of human PVSM cells with PDGF induced PI3K-dependent activation of Akt, S6K1, and ribosomal protein S6, but not MAPK. PDGF-induced proliferation and migration was inhibited by LY294002, a specific PI3K inhibitor, with an IC50 value of 1 µM and 3 µM, respectively. These results demonstrate that PI3K signaling is both necessary and sufficient to mediate human PVSM cell proliferation and migration, and suggest that the activation of PI3K may play an important role in vascular remodeling.
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