PI3K is required for proliferation and migration of human pulmonary vascular smooth muscle cells

Abstract

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; chi(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 signaling mediates vascular smooth muscle cell expression of periostin in vivo and in vitro

“…The PI3-kinase pathway is important for survival, replication, and migration of mammalian cells, including VSMCs (19)(20)(21). This pathway has been showed to be rapidly activated by growth factors such as PDGF and angiotensin II in vitro (20,21) and by mechanical vascular injury in vivo (17,18).…”

“…This pathway has been showed to be rapidly activated by growth factors such as PDGF and angiotensin II in vitro (20,21) and by mechanical vascular injury in vivo (17,18). Inhibition of the PI3-kinase/Akt signaling pathway has been showed to limit the neointima formation in rat vascular injury models.…”

Tuberin Regulates p70 S6 Kinase Activation and Ribosomal Protein S6 Phosphorylation

“…Expression of tuberin in these cells was confirmed by immunoblot analysis with anti-tuberin antibody (data not shown). ASM and VSM cells and HLF were dissociated from human trachea, human pulmonary artery, and human lung, respectively, which were obtained from human lung transplant donors and were previously described (36,37). ASM cells were maintained in Ham's F-12 with 10% FBS; VSM were maintained in Ham's F-12 with 10% FBS supplemented with 15 g/ml endothelial cell growth supplement (BD Biosciences), HLF were maintained in RPMI supplemented with 10% FBS.…”

The application of multiscale modelling to the process of development and prevention of stenosis in a stented coronary artery

“…The transcription factor nuclear factor kB operates downstream of both of these pathways. Care needs to be taken when extrapolating data from in vitro studies, as the precise contribution of individual pathways and the relationship between pathway and cellular response is species and cell type specific (Goncharova et al 2002). Activation of the PI3K/Akt pathway following stent implantation has also been observed in vivo (Zhou et al 2003).…”