Cellular Biology |
From the Departments of Pharmacology (M.M.-R., D.F., G.S., W.C.S.) and Pathology (L.R.L.) and Molecular Cardiobiology Program (M.M.-R., D.F., G.S., W.C.S.), Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, Conn, and Division of Cardiovascular Research (Y.F., K.W.), St Elizabeths Medical Center, Boston, Mass.
Correspondence to William C. Sessa, Yale University School of Medicine, Boyer Center for Molecular Medicine, 295 Congress Ave, New Haven, CT 06536-0812. E-mail william.sessa{at}yale.edu
| Abstract |
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Key Words: vascular endothelial growth factor angiogenesis cell migration nitric oxide actin
| Introduction |
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One downstream effector of PI(3) kinase is the serine/threonine kinase Akt (or protein kinase B).7 Upon receptor activation, Akt is recruited to the plasma membrane and binds to inositol lipids via its pleckstrin homology domain. Once in the membrane, Akt is phosphorylated by phosphoinositide-dependent kinases, and phosphorylation enhances its catalytic activity toward a variety of diverse substrates.8 Akt is an important regulator of various cellular processes, including metabolism and cell survival.9 Recently, we and others have shown that Akt can phosphorylate bovine endothelial NO synthase (eNOS) on serine 1179 (or serine 1177 in the human ortholog), resulting in eNOS activation and NO production.10 11 12 These findings, in addition to reports demonstrating a role for NO in endothelial cell migration promoted by growth factors such as endothelin and VEGF,13 14 15 suggested that the Akt/eNOS pathway functions to regulate endothelial cell migration. Therefore, we undertook the present study to examine whether the Akt/eNOS pathway participates in VEGF-induced endothelial cell migration, a necessary component of the angiogenic response.
| Materials and Methods |
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Adenoviral Constructs
ß-Galactosidase (ß-gal), hemagglutinin (HA)-tagged
inactive phosphorylation mutant Akt (AA-Akt), and
carboxyl-terminal HA-tagged constitutively active Akt (myr-Akt) were
generated as described previously.10 19 BLMVECs were
infected with 100 multiplicity of infection of adenovirus containing
ß-gal, AA-Akt, or myr-Akt for 12 hours. The virus was removed, and
cells were left to recover for 12 hours in complete medium. These
conditions resulted in uniform expression of the transgenes in close to
100% of the cells (determined by infection with ß-gal followed by
staining for ß-gal activity) and equal expression of Akt proteins,
based on Western blotting as described.10
Cell Migration Assay
Migration assays were performed as described previously using a
Boyden chamber (Neuroprobe).20 BLMVECs were infected with
adenoviruses for ß-gal. AA-Akt or myr-Akt, as described above, were
serum starved overnight and detached using trypsin (0.05%
vol/vol)/EDTA (0.53 mmol/L). Approximately 20 000 cells were
suspended in M199 containing BSA (0.1%) and were added to the lower
chamber. Polycarbonate filters (8-µm pores; Poretics Corp) were
coated with 100 µg/mL type I collagen (Collaborative Biomedical
Products). The top half of the chamber was attached, and the
chamber was incubated in an inverted position at 37°C for 2 hours to
allow uniform cell attachment to the filter. VEGF (1 to 100 ng/mL),
NG-nitro-L-arginine
methyl ester (L-NAME; 3 mmol/L),
NG-nitro-D-arginine
methyl ester (D-NAME; 3 mmol/L), or vehicle (M199 with
0.1% BSA) was added to the lower chamber. The chamber was incubated
for an additional 5 hours at 37°C. After incubation, cells were fixed
with ethanol (70%), and nonmigrating cells on the upper surface of the
filter were removed. Migrated cells were stained with Giemsa and
counted (at 400x magnification) in 3 random fields per well. Each
experiment was performed in triplicate, and migration was expressed as
the number of total cells counted per well. In some experiments,
BLMVECs were preincubated with or without L-NAME (3 mmol/L),
D-NAME (3 mmol/L), LY294002 (10 µmol/L), or wortmannin (100
nmol/L) for 30 minutes in M199 with 0.1% BSA at 37°C. In preliminary
experiments, this concentration of L-NAME, but not D-NAME, completely
blocked VEGF or calcium ionophorestimulated NO production or
cGMP accumulation in a reporter bioassay system as
described.18 21 22 In addition, the
concentrations of both LY294002 and wortmannin completely abolished
VEGF- or serum-stimulated Akt phosphorylation.
Adhesion Assay
Cell adhesion was assayed in 96-well plates precoated with type
I collagen (1, 3, 10, and 30 µg/mL) overnight, as previously
described23 (see also online-only expanded Materials and
Methods; http://www.circresaha.org).
Measurement of NO Release
For measurement of NO, the release of
NO2-, the stable breakdown
product of NO in aqueous medium, was determined as previously
described18 (see also online-only expanded Materials and
Methods; http://www.circresaha.org).
Confocal Fluorescence Microscopy
BLMVECs infected with adenoviruses for ß-gal, AA-Akt, or
myr-Akt were plated on gelatin-coated 35-mm plates (MatTek) as
previously described21 (see also online-only expanded
Materials and Methods; http://www.circresaha.org).
An expanded Materials and Methods section is available online at http://www.circresaha.org.
| Results and Discussion |
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Adhesion assays were performed to determine whether the effects of Akt
on endothelial cell migration could be attributed to
changes in cell adhesion to the collagen matrix. Figure 1B
shows
that BLMVECs transduced with ß-gal, AA-Akt, or myr-Akt adhered
similarly to collagen. Thus, the ability of the Akt transgenes to
influence cell migration were not due to effects on overall cell
adhesion.
VEGF-stimulated endothelial cell proliferation,
migration, and angiogenesis can be blocked by
L-argininesubstituted analogues that inhibit NO synthase
(NOS),14 24 and VEGF-induced angiogenesis is markedly
attenuated in eNOS knockout mice.25 Accordingly, we
examined the effects of the NOS inhibitor, L-NAME, or the
inactive D isomer, D-NAME, on basal and VEGF-stimulated cell migration
in endothelial cells infected with adenoviruses for
ß-gal or myr-Akt. In endothelial cells transduced
with ß-gal (Figure 2A
), VEGF
stimulated cell migration, an effect blocked by L-NAME but not by
D-NAME. L-NAME had no effect on basal migration, suggesting that VEGF
activation of NOS and the subsequent production of NO is
involved in cell migration. In contrast, myr-Akt markedly stimulated
basal endothelial cell migration, an effect that was
not influenced by L-NAME. Under these conditions, the NOS
inhibitor reduced myr-Aktstimulated
NO2 by >97% (n=3). However,
VEGF-stimulated cell migration in myr-Akttransduced BLMVECs was
blocked by L-NAME but not by D-NAME (Figure 2B
). These results
suggest that the Akt-NOS pathway is necessary for VEGF-induced cell
migration and that myr-Akt, while causing NO release, stimulates cell
migration in a NOS-independent manner.
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Cell migration is associated with regulation of the actin cytoskeleton.
As shown previously, VEGF induces edge ruffling22 and
stress fiber formation in cultured endothelial
cells.26 In quiescent BLMVECs infected with ß-gal,
F-actin was found mostly in membrane structures and unorganized fibers
throughout the cell (Figure 3
, left
panel, top). As expected, treatment with VEGF induced the formation of
long, condensed stress fibers (Figure 3
, right panel, top). To
explore the possibility that VEGF signals through Akt lead to stress
fiber formation, BLMVECs were transduced with AA-Akt and myr-Akt, and
the effects of VEGF were examined. As seen in control cells infected
with AA-Akt, there was less structured F-actin compared with cells
infected with ß-gal (Figure 3
, left panel, middle).
Importantly, VEGF-stimulated stress fiber formation was markedly
attenuated in cells expressing AA-Akt (Figure 3
, right panel,
middle). Furthermore, infection of BLMVECs with adenoviral myr-Akt
induces stress fiber formation and reorganization of F-actin (Figure 3
, left panel, bottom). Because of the profound effect of
myr-Akt by itself on F-actin, it was difficult to visualize
VEGF-stimulated rearrangement of the actin cytoskeleton (Figure 3
, right panel, bottom). These data indicate that VEGF-induced
cell migration and F-actin rearrangement are dependent on Akt and that
constitutively activated Akt is sufficient to cause cell
migration most likely because of its effects on stress fiber
formation.
|
To our knowledge, these results are the first to demonstrate a critical role for Akt in the migration of mammalian cells. Our findings demonstrating that Akt is important for endothelial cell migration are supported by various studies demonstrating a role of PI(3) kinase in cell migration4 5 and by a recent study in Dictyostelium showing that Akt is required for migration of cells toward the chemoattractant cAMP.27
In the present study, VEGF-induced Akt activation, NO production, stress fiber formation, and migration appear to lie in a common pathway, given that activation-deficient Akt attenuates all of these responses. The importance of the VEGF/Akt/eNOS pathway is supported by the observations that inhibition of NOS blocks VEGF-driven NO release, endothelial cell migration, formation of endothelial tubelike structures in vitro, and angiogenesis in vivo.14 23 28 29 In the context of cell motility, the effectors of NO are not known; however, NO can influence the tractional forces in activated endothelial cells and influence remodeling of focal adhesions, perhaps by influencing tyrosine phosphorylation of focal adhesion kinase.15 The link between eNOS, Akt, and signaling through the small G protein Rho as a primary mechanism leading to stress fiber formation during cell migration is not known and is presently being explored. In addition, NO may modulate the activation of the p38 mitogen-activated protein kinase (MAPK)/MAPK-activated protein kinase/Hsp27 pathway that is crucial for VEGF-induced endothelial cell chemotaxis.26
However, Akt activation of eNOS via phosphorylation and NO release is necessary for physiological migration in response to VEGF but is not sufficient for cell migration, based on our data with constitutively active Akt. Transduction of BLMVECs with myr-Akt markedly stimulated cell migration and profoundly affected cytoskeletal structure in the absence of VEGF. Surprisingly, inhibition of eNOS by L-NAME at concentrations that effectively block NO release18 21 25 had no influence on myr-Aktstimulated cell migration. These observations present a paradox. On the one hand, both Akt activation and NO production are essential for the physiological migratory response to VEGF, yet on the other hand, NO is dispensable for migration induced by myr-Akt. In the context of constitutive activation, Akt must trigger separate but interacting pathways that lead to cell migration. Presumably, the persistent plasma membrane localization of myr-Akt, resembling the N-myristoylated oncogenic variant v-Akt,30 31 results in the unregulated, sustained activation of ancillary signaling pathway different from those activated by the transient association of cellular Akt with the plasma membrane.32 33
In summary, VEGF can stimulate eNOS-derived NO production that
is physiologically linked to cell migration.
Upon activation of the VEGF receptor, activation of PI(3) kinase
(pathway A in Figure 4
) results in the
PI(3) kinasedependent phosphorylation of Akt,
resulting in the phosphorylation of eNOS on serine
1179. Because AMP-activated protein kinase can also
phosphorylate eNOS on the same residue, it is feasible that
activation of this pathway by metabolic stress may trigger
eNOS activation and cell migration.34 Concomitantly, VEGF
receptor engagement stimulates c-Srcdependent activation of
phospholipase C-
(PLC-
)35 (pathway B in
Figure 4
), resulting in an increase in cytoplasmic calcium. The
increase in calcium activates calmodulin, thus
enhancing the activity of phosphorylated eNOS.
Paradoxically, myr-Akt, in the absence of VEGF, triggers NO release and
cell migration; however, NO does not participate in the migratory
response, because L-NAME at concentrations that effectively block NO
release does not influence myr-Aktdriven migration (pathway C in
Figure 4
). Thus, this study highlights the
physiological importance of the Akt/NOS pathway for
VEGF-induced endothelial cell migration and
demonstrates a novel function for Akt in controlling cell migration.
Exploitation of this mechanism by selective inhibition of eNOS or Akt
may provide a rationale for antiangiogenic therapy in the treatment of
solid tumors.
|
| Acknowledgments |
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Received December 8, 1999; accepted February 16, 2000.
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Y. M. Kim, K. E. Kim, G. Y. Koh, Y.-S. Ho, and K.-J. Lee Hydrogen peroxide produced by angiopoietin-1 mediates angiogenesis. Cancer Res., June 15, 2006; 66(12): 6167 - 6174. [Abstract] [Full Text] [PDF] |
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S. Sanderson, M. Valenti, S. Gowan, L. Patterson, Z. Ahmad, P. Workman, and S. A. Eccles Benzoquinone ansamycin heat shock protein 90 inhibitors modulate multiple functions required for tumor angiogenesis. Mol. Cancer Ther., March 1, 2006; 5(3): 522 - 532. [Abstract] [Full Text] [PDF] |
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M. Jerkic, A. Rodriguez-Barbero, M. Prieto, M. Toporsian, M. Pericacho, J. V. Rivas-Elena, J. Obreo, A. Wang, F. Perez-Barriocanal, M. Arevalo, et al. Reduced angiogenic responses in adult endoglin heterozygous mice Cardiovasc Res, March 1, 2006; 69(4): 845 - 854. [Abstract] [Full Text] [PDF] |
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J. Segarra, L. Balenci, T. Drenth, F. Maina, and F. Lamballe Combined Signaling through ERK, PI3K/AKT, and RAC1/p38 Is Required for Met-triggered Cortical Neuron Migration J. Biol. Chem., February 24, 2006; 281(8): 4771 - 4778. [Abstract] [Full Text] [PDF] |
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F. G. Buchanan, D. L. Gorden, P. Matta, Q. Shi, L. M. Matrisian, and R. N. DuBois Role of beta-arrestin 1 in the metastatic progression of colorectal cancer PNAS, January 31, 2006; 103(5): 1492 - 1497. [Abstract] [Full Text] [PDF] |
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A. Uruno, A. Sugawara, H. Kanatsuka, H. Kagechika, A. Saito, K. Sato, M. Kudo, K. Takeuchi, and S. Ito Upregulation of Nitric Oxide Production in Vascular Endothelial Cells by All-trans Retinoic Acid Through the Phosphoinositide 3-Kinase/Akt Pathway Circulation, August 2, 2005; 112(5): 727 - 736. [Abstract] [Full Text] [PDF] |
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J. F. Grehan, B. K. Levay-Young, J. L. Fogelson, V. Francois-Bongarcon, B. A. Benson, and A. P. Dalmasso IL-4 and IL-13 Induce Protection of Porcine Endothelial Cells from Killing by Human Complement and from Apoptosis through Activation of a Phosphatidylinositide 3-Kinase/Akt Pathway J. Immunol., August 1, 2005; 175(3): 1903 - 1910. [Abstract] [Full Text] [PDF] |
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K. N. Sulochana, H. Fan, S. Jois, V. Subramanian, F. Sun, R. M. Kini, and R. Ge Peptides Derived from Human Decorin Leucine-rich Repeat 5 Inhibit Angiogenesis J. Biol. Chem., July 29, 2005; 280(30): 27935 - 27948. [Abstract] [Full Text] [PDF] |
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J. S. Lee, N. Kang Decker, S. Chatterjee, J. Yao, S. Friedman, and V. Shah Mechanisms of Nitric Oxide Interplay with Rho GTPase Family Members in Modulation of Actin Membrane Dynamics in Pericytes and Fibroblasts Am. J. Pathol., June 1, 2005; 166(6): 1861 - 1870. [Abstract] [Full Text] [PDF] |
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M. Bosch-Marce, R. Pola, A. B Wecker, M. Silver, A. Weber, C. Luedemann, C. Curry, T. Murayama, M. Kearney, Y.-s. Yoon, et al. Hyperhomocyst(e)inemia impairs angiogenesis in a murine model of limb ischemia Vascular Medicine, February 1, 2005; 10(1): 15 - 22. [Abstract] [PDF] |
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T. Yamazaki, T. Akada, O. Niizeki, T. Suzuki, H. Miyashita, and Y. Sato Puromycin-insensitive leucyl-specific aminopeptidase (PILSAP) binds and catalyzes PDK1, allowing VEGF-stimulated activation of S6K for endothelial cell proliferation and angiogenesis Blood, October 15, 2004; 104(8): 2345 - 2352. [Abstract] [Full Text] [PDF] |
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R.-H. Zhou, M. Yao, T.-S. Lee, Y. Zhu, M. Martins-Green, and J. Y.-J. Shyy Vascular Endothelial Growth Factor Activation of Sterol Regulatory Element Binding Protein: A Potential Role in Angiogenesis Circ. Res., September 3, 2004; 95(5): 471 - 478. [Abstract] [Full Text] [PDF] |
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H. Kim, Q. Li, B. L. Hempstead, and J. A. Madri Paracrine and Autocrine Functions of Brain-derived Neurotrophic Factor (BDNF) and Nerve Growth Factor (NGF) in Brain-derived Endothelial Cells J. Biol. Chem., August 6, 2004; 279(32): 33538 - 33546. [Abstract] [Full Text] [PDF] |
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N. Ferrara Vascular Endothelial Growth Factor: Basic Science and Clinical Progress Endocr. Rev., August 1, 2004; 25(4): 581 - 611. [Abstract] [Full Text] [PDF] |
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S. Gingis-Velitski, A. Zetser, M. Y. Flugelman, I. Vlodavsky, and N. Ilan Heparanase Induces Endothelial Cell Migration via Protein Kinase B/Akt Activation J. Biol. Chem., May 28, 2004; 279(22): 23536 - 23541. [Abstract] [Full Text] [PDF] |
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J.-H. Ahn, J.-S. Kim, H.-K. Yu, H.-J. Lee, and Y. Yoon A Truncated Kringle Domain of Human Apolipoprotein(a) Inhibits the Activation of Extracellular Signal-regulated Kinase 1 and 2 through a Tyrosine Phosphatase-dependent Pathway J. Biol. Chem., May 21, 2004; 279(21): 21808 - 21814. [Abstract] [Full Text] [PDF] |
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C.-H. Cho, C. S. Lee, M. Chang, I.-H. Jang, S. J. Kim, I. Hwang, S. H. Ryu, C. O. Lee, and G. Y. Koh Localization of VEGFR-2 and PLD2 in endothelial caveolae is involved in VEGF-induced phosphorylation of MEK and ERK Am J Physiol Heart Circ Physiol, May 1, 2004; 286(5): H1881 - H1888. [Abstract] [Full Text] [PDF] |
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J.-x. Chen, M. L. Lawrence, G. Cunningham, B. W. Christman, and B. Meyrick HSP90 and Akt modulate Ang-1-induced angiogenesis via NO in coronary artery endothelium J Appl Physiol, February 1, 2004; 96(2): 612 - 620. [Abstract] [Full Text] [PDF] |
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A. Papapetropoulos, D. Fulton, M. I. Lin, J. Fontana, T. J. McCabe, S. Zoellner, G. Garcia-Cardena, Z. Zhou, J.-P. Gratton, and W. C. Sessa Vanadate Is a Potent Activator of Endothelial Nitric-Oxide Synthase: Evidence for the Role of the Serine/Threonine Kinase Akt and the 90-kDa Heat Shock Protein Mol. Pharmacol., February 1, 2004; 65(2): 407 - 415. [Abstract] [Full Text] [PDF] |
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N. Ouchi, H. Kobayashi, S. Kihara, M. Kumada, K. Sato, T. Inoue, T. Funahashi, and K. Walsh Adiponectin Stimulates Angiogenesis by Promoting Cross-talk between AMP-activated Protein Kinase and Akt Signaling in Endothelial Cells J. Biol. Chem., January 9, 2004; 279(2): 1304 - 1309. [Abstract] [Full Text] [PDF] |
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Y. Qian, L. Corum, Q. Meng, J. Blenis, J. Z. Zheng, X. Shi, D. C. Flynn, and B.-H. Jiang PI3K induced actin filament remodeling through Akt and p70S6K1: implication of essential role in cell migration Am J Physiol Cell Physiol, January 1, 2004; 286(1): C153 - C163. [Abstract] [Full Text] [PDF] |
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Y. Taniyama, D. S. Weber, P. Rocic, L. Hilenski, M. L. Akers, J. Park, B. A. Hemmings, R. W. Alexander, and K. K. Griendling Pyk2- and Src-Dependent Tyrosine Phosphorylation of PDK1 Regulates Focal Adhesions Mol. Cell. Biol., November 15, 2003; 23(22): 8019 - 8029. [Abstract] [Full Text] [PDF] |
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G.-L. Zhou, Y. Zhuo, C. C. King, B. H. Fryer, G. M. Bokoch, and J. Field Akt Phosphorylation of Serine 21 on Pak1 Modulates Nck Binding and Cell Migration Mol. Cell. Biol., November 15, 2003; 23(22): 8058 - 8069. [Abstract] [Full Text] [PDF] |
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I. Adini, I. Rabinovitz, J. F. Sun, G. C. Prendergast, and L. E. Benjamin RhoB controls Akt trafficking and stage-specific survival of endothelial cells during vascular development Genes & Dev., November 1, 2003; 17(21): 2721 - 2732. [Abstract] [Full Text] [PDF] |
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H. Maekawa, Y. Oike, S. Kanda, Y. Ito, Y. Yamada, H. Kurihara, R. Nagai, and T. Suda Ephrin-B2 Induces Migration of Endothelial Cells Through the Phosphatidylinositol-3 Kinase Pathway and Promotes Angiogenesis in Adult Vasculature Arterioscler Thromb Vasc Biol, November 1, 2003; 23(11): 2008 - 2014. [Abstract] [Full Text] [PDF] |
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M. J. Smit, P. Verdijk, E. M. H. van der Raaij-Helmer, M. Navis, P. J. Hensbergen, R. Leurs, and C. P. Tensen CXCR3-mediated chemotaxis of human T cells is regulated by a Gi- and phospholipase C-dependent pathway and not via activation of MEK/p44/p42 MAPK nor Akt/PI-3 kinase Blood, September 15, 2003; 102(6): 1959 - 1965. [Abstract] [Full Text] [PDF] |
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K. Kawasaki, R. S. Smith Jr., C.-M. Hsieh, J. Sun, J. Chao, and J. K. Liao Activation of the Phosphatidylinositol 3-Kinase/Protein Kinase Akt Pathway Mediates Nitric Oxide-Induced Endothelial Cell Migration and Angiogenesis Mol. Cell. Biol., August 15, 2003; 23(16): 5726 - 5737. [Abstract] [Full Text] [PDF] |
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D. Nagata, M. Mogi, and K. Walsh AMP-activated Protein Kinase (AMPK) Signaling in Endothelial Cells Is Essential for Angiogenesis in Response to Hypoxic Stress J. Biol. Chem., August 15, 2003; 278(33): 31000 - 31006. [Abstract] [Full Text] [PDF] |
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R. Das, G. H. Mahabeleshwar, and G. C. Kundu Osteopontin Stimulates Cell Motility and Nuclear Factor {kappa}B-mediated Secretion of Urokinase Type Plasminogen Activator through Phosphatidylinositol 3-Kinase/Akt Signaling Pathways in Breast Cancer Cells J. Biol. Chem., August 1, 2003; 278(31): 28593 - 28606. [Abstract] [Full Text] [PDF] |
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N. Bettache, L. Baisamy, S. Baghdiguian, B. Payrastre, P. Mangeat, and A. Bienvenue Mechanical constraint imposed on plasma membrane through transverse phospholipid imbalance induces reversible actin polymerization via phosphoinositide 3-kinase activation J. Cell Sci., June 1, 2003; 116(11): 2277 - 2284. [Abstract] [Full Text] [PDF] |
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M. Duval, S. Bedard-Goulet, C. Delisle, and J.-P. Gratton Vascular Endothelial Growth Factor-dependent Down-regulation of Flk-1/KDR Involves Cbl-mediated Ubiquitination: CONSEQUENCES ON NITRIC OXIDE PRODUCTION FROM ENDOTHELIAL CELLS J. Biol. Chem., May 23, 2003; 278(22): 20091 - 20097. [Abstract] [Full Text] [PDF] |
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G. Zauli, A. Pandolfi, A. Gonelli, R. Di Pietro, S. Guarnieri, G. Ciabattoni, R. Rana, M. Vitale, and P. Secchiero Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) Sequentially Upregulates Nitric Oxide and Prostanoid Production in Primary Human Endothelial Cells Circ. Res., April 18, 2003; 92(7): 732 - 740. [Abstract] [Full Text] [PDF] |
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H. Kook, H. Itoh, B. S. Choi, N. Sawada, K. Doi, T. J. Hwang, K. K. Kim, H. Arai, Y. H. Baik, and K. Nakao Physiological concentration of atrial natriuretic peptide induces endothelial regeneration in vitro Am J Physiol Heart Circ Physiol, April 1, 2003; 284(4): H1388 - H1397. [Abstract] [Full Text] [PDF] |
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Y.-T. Tai, K. Podar, N. Mitsiades, B. Lin, C. Mitsiades, D. Gupta, M. Akiyama, L. Catley, T. Hideshima, N. C. Munshi, et al. CD40 induces human multiple myeloma cell migration via phosphatidylinositol 3-kinase/AKT/NF-kappa B signaling Blood, April 1, 2003; 101(7): 2762 - 2769. [Abstract] [Full Text] [PDF] |
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T. Minami, Md. R. Abid, J. Zhang, G. King, T. Kodama, and W. C. Aird Thrombin Stimulation of Vascular Adhesion Molecule-1 in Endothelial Cells Is Mediated by Protein Kinase C (PKC)-delta -NF-kappa B and PKC-zeta -GATA Signaling Pathways J. Biol. Chem., February 21, 2003; 278(9): 6976 - 6984. [Abstract] [Full Text] [PDF] |
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A. Skaletz-Rorowski, M. Lutchman, Y. Kureishi, D. J. Lefer, J. R. Faust, and K. Walsh HMG-CoA reductase inhibitors promote cholesterol-dependent Akt/PKB translocation to membrane domains in endothelial cells Cardiovasc Res, January 1, 2003; 57(1): 253 - 264. [Abstract] [Full Text] [PDF] |
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A. Pedram, M. Razandi, and E. R. Levin Deciphering Vascular Endothelial Cell Growth Factor/Vascular Permeability Factor Signaling to Vascular Permeability. INHIBITION BY ATRIAL NATRIURETIC PEPTIDE J. Biol. Chem., November 8, 2002; 277(46): 44385 - 44398. [Abstract] [Full Text] [PDF] |
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S. Goetze, A. Bungenstock, C. Czupalla, F. Eilers, P. Stawowy, U. Kintscher, C. Spencer-Hansch, K. Graf, B. Nurnberg, R. E. Law, et al. Leptin Induces Endothelial Cell Migration Through Akt, Which Is Inhibited by PPAR{gamma}-Ligands Hypertension, November 1, 2002; 40(5): 748 - 754. [Abstract] [Full Text] [PDF] |
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H.-S. Kim, C. Skurk, S. R. Thomas, A. Bialik, T. Suhara, Y. Kureishi, M. Birnbaum, J. F. Keaney Jr., and K. Walsh Regulation of Angiogenesis by Glycogen Synthase Kinase-3beta J. Biol. Chem., October 25, 2002; 277(44): 41888 - 41896. [Abstract] [Full Text] [PDF] |
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N. M. Conus, K. M. Hannan, B. E. Cristiano, B. A. Hemmings, and R. B. Pearson Direct Identification of Tyrosine 474 as a Regulatory Phosphorylation Site for the Akt Protein Kinase J. Biol. Chem., October 4, 2002; 277(41): 38021 - 38028. [Abstract] [Full Text] [PDF] |
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W.-H. Zhu, A. MacIntyre, and R. F. Nicosia Regulation of Angiogenesis by Vascular Endothelial Growth Factor and Angiopoietin-1 in the Rat Aorta Model : Distinct Temporal Patterns of Intracellular Signaling Correlate with Induction of Angiogenic Sprouting Am. J. Pathol., September 1, 2002; 161(3): 823 - 830. [Abstract] [Full Text] [PDF] |
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I. Shiojima and K. Walsh Role of Akt Signaling in Vascular Homeostasis and Angiogenesis Circ. Res., June 28, 2002; 90(12): 1243 - 1250. [Abstract] [Full Text] [PDF] |
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D. H. Walter, K. Rittig, F. H. Bahlmann, R. Kirchmair, M. Silver, T. Murayama, H. Nishimura, D. W. Losordo, T. Asahara, and J. M. Isner Statin Therapy Accelerates Reendothelialization: A Novel Effect Involving Mobilization and Incorporation of Bone Marrow-Derived Endothelial Progenitor Cells Circulation, June 25, 2002; 105(25): 3017 - 3024. [Abstract] [Full Text] [PDF] |
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K. J. Purdie, G. St.J. Whitley, A. P. Johnstone, and J. E. Cartwright Hepatocyte growth factor-induced endothelial cell motility is mediated by the upregulation of inducible nitric oxide synthase expression Cardiovasc Res, June 1, 2002; 54(3): 659 - 668. [Abstract] [Full Text] [PDF] |
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A. Adini, T. Kornaga, F. Firoozbakht, and L. E. Benjamin Placental Growth Factor Is a Survival Factor for Tumor Endothelial Cells and Macrophages Cancer Res., May 1, 2002; 62(10): 2749 - 2752. [Abstract] [Full Text] [PDF] |
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C. Urbich, E. Dernbach, A. M. Zeiher, and S. Dimmeler Double-Edged Role of Statins in Angiogenesis Signaling Circ. Res., April 5, 2002; 90(6): 737 - 744. [Abstract] [Full Text] [PDF] |
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T. Suhara, H.-S. Kim, L. A. Kirshenbaum, and K. Walsh Suppression of Akt Signaling Induces Fas Ligand Expression: Involvement of Caspase and Jun Kinase Activation in Akt-Mediated Fas Ligand Regulation Mol. Cell. Biol., January 15, 2002; 22(2): 680 - 691. [Abstract] [Full Text] [PDF] |
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J.N. UPALAKALIN, I. HEMO, C. DEHIO, E. KESHET, and L.E. BENJAMIN Survival Mechanisms of VEGF and PlGF during Microvascular Remodeling Cold Spring Harb Symp Quant Biol, January 1, 2002; 67(0): 181 - 188. [Abstract] [PDF] |
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C. Urbich, E. Dernbach, A. Reissner, M. Vasa, A. M. Zeiher, and S. Dimmeler Shear Stress-Induced Endothelial Cell Migration Involves Integrin Signaling Via the Fibronectin Receptor Subunits {alpha}5 and {beta}1 Arterioscler Thromb Vasc Biol, January 1, 2002; 22(1): 69 - 75. [Abstract] [Full Text] [PDF] |
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P. M. Becker, A. D. Verin, M. A. Booth, F. Liu, A. Birukova, and J. G. N. Garcia Differential regulation of diverse physiological responses to VEGF in pulmonary endothelial cells Am J Physiol Lung Cell Mol Physiol, December 1, 2001; 281(6): L1500 - L1511. [Abstract] [Full Text] [PDF] |
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A. P. McLaughlin and G. W. De Vries Role of PLCgamma and Ca2+ in VEGF- and FGF-induced choroidal endothelial cell proliferation Am J Physiol Cell Physiol, November 1, 2001; 281(5): C1448 - C1456. [Abstract] [Full Text] [PDF] |
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D. A. Flusberg, Y. Numaguchi, and D. E. Ingber Cooperative Control of Akt Phosphorylation, bcl-2 Expression, and Apoptosis by Cytoskeletal Microfilaments and Microtubules in Capillary Endothelial Cells Mol. Biol. Cell, October 1, 2001; 12(10): 3087 - 3094. [Abstract] [Full Text] [PDF] |
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T. Hayashibara, Y. Yamada, T. Miyanishi, H. Mori, T. Joh, T. Maeda, N. Mori, T. Maita, S. Kamihira, and M. Tomonaga Vascular Endothelial Growth Factor and Cellular Chemotaxis: A Possible Autocrine Pathway in Adult T-Cell Leukemia Cell Invasion Clin. Cancer Res., September 1, 2001; 7(9): 2719 - 2726. [Abstract] [Full Text] [PDF] |
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F. Liu, A. D. Verin, P. Wang, R. Day, R. P. Wersto, F. J. Chrest, D. K. English, and J. G. N. Garcia Differential Regulation of Sphingosine-1-Phosphate- and VEGF-Induced Endothelial Cell Chemotaxis . Involvement of Gialpha 2-Linked Rho Kinase Activity Am. J. Respir. Cell Mol. Biol., June 1, 2001; 24(6): 711 - 719. [Abstract] [Full Text] [PDF] |
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M. Mesri, M. Morales-Ruiz, E. J. Ackermann, C. F. Bennett, J. S. Pober, W. C. Sessa, and D. C. Altieri Suppression of Vascular Endothelial Growth Factor-Mediated Endothelial Cell Protection by Survivin Targeting Am. J. Pathol., May 1, 2001; 158(5): 1757 - 1765. [Abstract] [Full Text] [PDF] |
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E. Chavakis, E. Dernbach, C. Hermann, U. F. Mondorf, A. M. Zeiher, and S. Dimmeler Oxidized LDL Inhibits Vascular Endothelial Growth Factor-Induced Endothelial Cell Migration by an Inhibitory Effect on the Akt/Endothelial Nitric Oxide Synthase Pathway Circulation, April 24, 2001; 103(16): 2102 - 2107. [Abstract] [Full Text] [PDF] |
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H. Nakagami, R. Morishita, K. Yamamoto, Y. Taniyama, M. Aoki, K. Matsumoto, T. Nakamura, Y. Kaneda, M. Horiuchi, and T. Ogihara Mitogenic and Antiapoptotic Actions of Hepatocyte Growth Factor Through ERK, STAT3, and Akt in Endothelial Cells Hypertension, February 1, 2001; 37(2): 581 - 586. [Abstract] [Full Text] [PDF] |
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S. Dimmeler and A. M. Zeiher Endothelial Cell Apoptosis in Angiogenesis and Vessel Regression Circ. Res., September 15, 2000; 87(6): 434 - 439. [Abstract] [Full Text] [PDF] |
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D.-Q. Zheng, A. S. Woodard, G. Tallini, and L. R. Languino Substrate Specificity of alpha vbeta 3 Integrin-mediated Cell Migration and Phosphatidylinositol 3-Kinase/AKT Pathway Activation J. Biol. Chem., August 4, 2000; 275(32): 24565 - 24574. [Abstract] [Full Text] [PDF] |
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M. A. Reddy, N. V. Prasadarao, C. A. Wass, and K. S. Kim Phosphatidylinositol 3-Kinase Activation and Interaction with Focal Adhesion Kinase in Escherichia coli K1 Invasion of Human Brain Microvascular Endothelial Cells J. Biol. Chem., November 17, 2000; 275(47): 36769 - 36774. [Abstract] [Full Text] [PDF] |
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J.-P. Gratton, M. Morales-Ruiz, Y. Kureishi, D. Fulton, K. Walsh, and W. C. Sessa Akt Down-regulation of p38 Signaling Provides a Novel Mechanism of Vascular Endothelial Growth Factor-mediated Cytoprotection in Endothelial Cells J. Biol. Chem., August 3, 2001; 276(32): 30359 - 30365. [Abstract] [Full Text] [PDF] |
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I. Kim, S.-O. Moon, S. Hoon Kim, H. Jin Kim, Y. Soon Koh, and G. Young Koh Vascular Endothelial Growth Factor Expression of Intercellular Adhesion Molecule 1 (ICAM-1), Vascular Cell Adhesion Molecule 1 (VCAM-1), and E-selectin through Nuclear Factor-kappa B Activation in Endothelial Cells J. Biol. Chem., March 2, 2001; 276(10): 7614 - 7620. [Abstract] [Full Text] [PDF] |
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M. Morales-Ruiz, M.-J. Lee, S. Zollner, J.-P. Gratton, R. Scotland, I. Shiojima, K. Walsh, T. Hla, and W. C. Sessa Sphingosine 1-Phosphate Activates Akt, Nitric Oxide Production, and Chemotaxis through a Gi Protein/Phosphoinositide 3-Kinase Pathway in Endothelial Cells J. Biol. Chem., May 25, 2001; 276(22): 19672 - 19677. [Abstract] [Full Text] [PDF] |
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N. J. MacDonald, W. Y. Shivers, D. L. Narum, S. M. Plum, J. N. Wingard, S. R. Fuhrmann, H. Liang, J. Holland-Linn, D. H. T. Chen, and B. K. L. Sim Endostatin Binds Tropomyosin. A POTENTIAL MODULATOR OF THE ANTITUMOR ACTIVITY OF ENDOSTATIN J. Biol. Chem., June 29, 2001; 276(27): 25190 - 25196. [Abstract] [Full Text] [PDF] |
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K. N. Meadows, P. Bryant, and K. Pumiglia Vascular Endothelial Growth Factor Induction of the Angiogenic Phenotype Requires Ras Activation J. Biol. Chem., December 21, 2001; 276(52): 49289 - 49298. [Abstract] [Full Text] [PDF] |
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D. Thuringer, L. Maulon, and C. Frelin Rapid Transactivation of the Vascular Endothelial Growth Factor Receptor KDR/Flk-1 by the Bradykinin B2 Receptor Contributes to Endothelial Nitric-oxide Synthase Activation in Cardiac Capillary Endothelial Cells J. Biol. Chem., January 11, 2002; 277(3): 2028 - 2032. [Abstract] [Full Text] [PDF] |
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T. Suhara, T. Mano, B. E. Oliveira, and K. Walsh Phosphatidylinositol 3-Kinase/Akt Signaling Controls Endothelial Cell Sensitivity to Fas-Mediated Apoptosis via Regulation of FLICE-Inhibitory Protein (FLIP) Circ. Res., July 6, 2001; 89(1): 13 - 19. [Abstract] [Full Text] [PDF] |
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M. Vasa, S. Fichtlscherer, K. Adler, A. Aicher, H. Martin, A. M. Zeiher, and S. Dimmeler Increase in Circulating Endothelial Progenitor Cells by Statin Therapy in Patients With Stable Coronary Artery Disease Circulation, June 19, 2001; 103(24): 2885 - 2890. [Abstract] [Full Text] [PDF] |
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C. Urbich, E. Dernbach, A. M. Zeiher, and S. Dimmeler Double-Edged Role of Statins in Angiogenesis Signaling Circ. Res., April 5, 2002; 90(6): 737 - 744. [Abstract] [Full Text] [PDF] |
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