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1 Pulmonary, Allergy, and Critical Care Division, Department of Medicine; and 2 Abramson Family Cancer Research Institute, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104-6160
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 phosphatidylinositol 3-kinase (PI3K)
activation is both necessary and sufficient to mediate human pulmonary
vascular smooth muscle (PVSM) cell proliferation and migration.
Microinjection of human PVSM cells with a dominant-negative class IA
PI3K inhibited platelet-derived growth factor (PDGF)-induced DNA
synthesis by 65% (P < 0.001; 
2
analysis) compared with cells microinjected with control plasmid, whereas microinjection of cells with a constitutively active class IA
PI3K (p110*-CA) was sufficient to induce DNA synthesis (mitotic index
of p110*-CA-microinjected cells was 15% vs. 3% in control cells;
P < 0.01). 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, p70 S6 kinase, and ribosomal protein
S6 but not mitogen-activated protein kinase. PDGF-induced proliferation
and migration was inhibited by LY-294002. 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.
phosphatidylinositol 3-kinase; hypertension; Akt; S6K1; ribosomal protein S6
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