Activation of the Phosphatidylinositol 3-Kinase/Protein Kinase Akt Pathway Mediates Nitric Oxide-Induced Endothelial Cell Migration and Angiogenesis

Abstract

To test the hypothesis that the phosphatidylinositol 3-kinase (PI3 kinase)/protein kinase Akt signaling pathway is involved in nitric oxide (NO)-induced endothelial cell migration and angiogenesis, we treated human and bovine endothelial cells with NO donors, S-nitroso-L-glutathione (GSNO) and S-nitroso-N-penicillamine (SNAP). Both GSNO and SNAP increased Akt phosphorylation and activity, which were blocked by cotreatment with the PI3 kinase inhibitor wortmannin. The mechanism was due to the activation of soluble guanylyl cyclase because 8-bromo-cyclic GMP activated PI3 kinase and the soluble guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-␣]quinoxalin-1-one (ODQ) blocked NO-induced PI3 kinase activity. Indeed, transfection with adenovirus containing endothelial cell NO synthase (eNOS) or protein kinase G (PKG) increased endothelial cell migration, which was inhibited by cotransfection with a dominant-negative mutant of PI3 kinase (dnPI3 kinase). In a rat model of hind limb ischemia, adenovirus-mediated delivery of human eNOS cDNA in adductor muscles resulted in time-dependent expression of recombinant eNOS, which was accompanied by significant increases in regional blood perfusion and capillary density. Coinjection of adenovirus carrying dnPI3 kinase abolished neovascularization in ischemic hind limb induced by eNOS gene transfer. These findings indicate that NO promotes endothelial cell migration and neovascularization via cGMP-dependent activation of PI3 kinase and suggest that this pathway is important in mediating NO-induced angiogenesis.

Arachidonic Acid Epoxygenase Metabolites Stimulate Endothelial Cell Growth and Angiogenesis via Mitogen-Activated Protein Kinase and Phosphatidylinositol 3-Kinase/Akt Signaling Pathways

“…Addition of L-NMMA to cultures of BAECs attenuated the EET-and AA epoxygenase-induced migration and proliferation of these cells, suggesting that eNOS up-regulation may mediate, at least in part, the angiogenic effects of EETs. We also demonstrated that inhibitors of the PI3-kinase/Akt pathway significantly attenuated the EET-mediated angiogenic effects, consistent with the concept that the PI3-kinase/Akt pathway may mediate the angiogenic effects of NO (Kawasaki et al, 2003).…”

“…NO and endothelium-derived hyperpolarizing factor represent the two major endothelial autacoids involved in the local control of vascular tone (Bauersachs et al, 1997). Importantly, the angiogenic effects of NO have been shown to be mediated by activation of the PI3-kinase/Akt pathway (Kawasaki et al, 2003).…”

“…The differential response to EETs in vascular smooth muscle cells and endothelial cells may be due to tissue specificity of EET activity. Indeed, cAMP is elevated in the former cell types whereas cGMP is elevated in the latter cell types due to G protein stimulation and activation of MAPK and Akt (Kawasaki et al, 2003).…”

Low‐energy laser irradiation increases endothelial cell proliferation, migration, and eNOS gene expression possibly via PI3K signal pathway

“…5). This mechanism agreed with the previous finding that EC expressed the constitutive eNOS through pathway to form NO and showed an increased migration in the process of angiogenesis [58]. A distinct signal generated by KDR, which influences cell migration by regulating cell adhesion via the assembly of vinculin on EC, has been found in a recent study [59].…”

Commutators of PAR-1 signaling in cancer cell invasion reveal an essential role of the Rho–Rho kinase axis and tumor microenvironment

“…The hypoxia-dependent angiogenic switch in human solid tumors is an early event linked to the secretion of high levels of VEGF and several angiogenic factors by cancer cells, as well as by endothelial cells or other cell types in the tumor stroma (Andre et al, 2000). The NO/cGMP/ PKG and calcium-dependent signaling pathways are also involved in the regulation of tumor cell invasiveness and angiogenesis linked to endothelial cell proliferation, morphogenesis, and tumor invasion (Kawasaki et al, 2003). These observations led to the hypothesis that hypoxic conditions could exert a direct or a permissive role on the PAR-1 invasive potential.…”