© 2000 American Heart Association, Inc.
Editorials |
Akt Takes Center Stage in Angiogenesis Signaling
From Molecular Cardiology, Department of Internal Medicine IV, University of Frankfurt, Germany.
Correspondence to Stefanie Dimmeler, PhD, Molecular Cardiology, Department of Internal Medicine IV, University of Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany. E-mail Dimmeler@em.uni-frankfurt.de
Key Words: protein kinase B • angiopoietin • vascular endothelial growth factor • nitric oxide • apoptosis
 |
Introduction |
|---|
The serine/threonine kinase Akt, also named protein kinase B, plays a central role in promoting the survival of a wide range of cell types.1 In this issue of Circulation Research, Kim et al2 report that angiopoietin-1 (Ang1) activates this survival kinase and thereby inhibits endothelial cell apoptosis. Ang1 was recently identified as the specific ligand for the Tie receptor family, which during embryonic blood vessel formation is required for vascular remodeling and vessel integrity.3 Mechanistically, Ang1 acts via stimulation of the Tie2 receptor. Upon activation, tyrosine phosphorylation of the Tie2 receptor (most probably at Tyr 11014 ) induces the association and activation of the phosphatidylinositol 3'kinase with subsequent activation of Akt.2 These findings complement previous studies, which demonstrated that vascular endothelial growth factor (VEGF) via the KDR/Flt-1 receptor also stimulates Akt and thereby promotes endothelial cell survival.5 6 Moreover, potent inhibitors of endothelial cell apoptosis such as shear stress or insulin activate Akt.7 8 Thus, activation of Akt seems to be a general antiapoptotic mechanism induced by proangiogenic stimuli. Because apoptosis of endothelial cells counteracts angiogenesis, one may also speculate that signaling pathways leading to apoptosis suppression may significantly contribute to angiogenesis, a process required for the revascularization of ischemic tissue.
Although the contribution of Akt in angiogenesis is still an open
question, several lines of evidence suggest a link between Akt and
angiogenesis. Thus, Akt has recently been shown to
phosphorylate the endothelial nitric oxide
synthase (eNOS) leading to a persistent, calcium-independent enzyme
activation.9 10 A large body of literature indicates
This article has been cited by other articles:
 |
|
 |
|
  R.I. Soden, T.M. Botero, C.T. Hanks, and J.E. Nor Angiogenic Signaling Triggered by Cariogenic Bacteria in Pulp Cells Journal of Dental Research, September 1, 2009; 88(9): 835 - 840. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. S. Smith Jr., L. Gao, G. Bledsoe, L. Chao, and J. Chao Intermedin is a new angiogenic growth factor Am J Physiol Heart Circ Physiol, September 1, 2009; 297(3): H1040 - H1047. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Kang, K. J. Bayless, and R. Kaunas Fluid shear stress modulates endothelial cell invasion into three-dimensional collagen matrices Am J Physiol Heart Circ Physiol, November 1, 2008; 295(5): H2087 - H2097. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Chetty, S. S. Lakka, P. Bhoopathi, S. Kunigal, R. Geiss, and J. S. Rao Tissue Inhibitor of Metalloproteinase 3 Suppresses Tumor Angiogenesis in Matrix Metalloproteinase 2-Down-regulated Lung Cancer Cancer Res., June 15, 2008; 68(12): 4736 - 4745. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Rodriguez-Yanez, J. Agulla, R. Rodriguez-Gonzalez, T. Sobrino, and J. Castillo Review: Statins and stroke Therapeutic Advances in Cardiovascular Disease, June 1, 2008; 2(3): 157 - 166. [Abstract] [PDF]
|
|
|
|
 |
|
 D. You, C. Cochain, C. Loinard, J. Vilar, B. Mees, M. Duriez, B. I. Levy, and J.-S. Silvestre Combination of the Angiotensin-Converting Enzyme Inhibitor Perindopril and the Diuretic Indapamide Activate Postnatal Vasculogenesis in Spontaneously Hypertensive Rats J. Pharmacol. Exp. Ther., June 1, 2008; 325(3): 766 - 773. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. E. Hoefer Something is rotten in the state of angiogenesis -- H2S as gaseous stimulator of angiogenesis Cardiovasc Res, October 1, 2007; 76(1): 1 - 2. [Full Text] [PDF]
|
|
|
|
 |
|
 M. Artwohl, K. Muth, K. Kosulin, R. de Martin, T. Holzenbein, G. Rainer, A. Freudenthaler, N. Huttary, L. Schmetterer, W. K. Waldhausl, et al. R-(+)-{alpha}-lipoic acid inhibits endothelial cell apoptosis and proliferation: involvement of Akt and retinoblastoma protein/E2F-1 Am J Physiol Endocrinol Metab, September 1, 2007; 293(3): E681 - E689. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Liu, Y. Jiang, H. Hao, K. Gupta, J. Xu, L. Chu, E. McFalls, J. Zweier, C. Verfaillie, and R. J. Bache Endothelial nitric oxide synthase is dynamically expressed during bone marrow stem cell differentiation into endothelial cells Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1760 - H1765. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. S.N. Shim, I. A.W. Ho, and P. E.H. Wong Angiopoietin: A TIE(d) Balance in Tumor Angiogenesis Mol. Cancer Res., July 1, 2007; 5(7): 655 - 665. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Ribatti, M. T. Conconi, and G. G. Nussdorfer Nonclassic Endogenous Novel Regulators of Angiogenesis Pharmacol. Rev., June 1, 2007; 59(2): 185 - 205. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Li, S. Hazarika, D. Xie, A. M. Pippen, C. D. Kontos, and B. H. Annex In Mice With Type 2 Diabetes, a Vascular Endothelial Growth Factor (VEGF)-Activating Transcription Factor Modulates VEGF Signaling and Induces Therapeutic Angiogenesis After Hindlimb Ischemia Diabetes, March 1, 2007; 56(3): 656 - 665. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-X. Chen, H. Zeng, M. L Lawrence, T. S. Blackwell, and B. Meyrick Angiopoietin-1-induced angiogenesis is modulated by endothelial NADPH oxidase Am J Physiol Heart Circ Physiol, October 1, 2006; 291(4): H1563 - H1572. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Iemitsu, S. Maeda, S. Jesmin, T. Otsuki, and T. Miyauchi Exercise training improves aging-induced downregulation of VEGF angiogenic signaling cascade in hearts Am J Physiol Heart Circ Physiol, September 1, 2006; 291(3): H1290 - H1298. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Uemura, M. Xu, N. Ahmad, and M. Ashraf Bone Marrow Stem Cells Prevent Left Ventricular Remodeling of Ischemic Heart Through Paracrine Signaling Circ. Res., June 9, 2006; 98(11): 1414 - 1421. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-S. Silvestre and B. I. Levy Molecular Basis of Angiopathy in Diabetes Mellitus Circ. Res., January 6, 2006; 98(1): 4 - 6. [Full Text] [PDF]
|
|
|
|
|
|
J. Muller-Ehmsen, A. Schmidt, B. Krausgrill, R. H. G. Schwinger, and W. Bloch Role of erythropoetin for angiogenesis and vasculogenesis: from embryonic development through adulthood Am J Physiol Heart Circ Physiol, January 1, 2006; 290(1): H331 - H340. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X.-L. Cui, A. M. Schlesier, E. L. Fisher, C. Cerqueira, and R. P. Ferraris Fructose-induced increases in neonatal rat intestinal fructose transport involve the PI3-kinase/Akt signaling pathway Am J Physiol Gastrointest Liver Physiol, June 1, 2005; 288(6): G1310 - G1320. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 H.-P. Lin, S. K. Kulp, P.-H. Tseng, Y.-T. Yang, C.-C. Yang, C.-S. Chen, and C.-S. Chen Growth inhibitory effects of celecoxib in human umbilical vein endothelial cells are mediated through G1 arrest via multiple signaling mechanisms Mol. Cancer Ther., December 1, 2004; 3(12): 1671 - 1680. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 F. H. Bahlmann, R. Song, S. M. Boehm, M. Mengel, R. von Wasielewski, C. Lindschau, T. Kirsch, K. de Groot, R. Laudeley, E. Niemczyk, et al. Low-Dose Therapy With the Long-Acting Erythropoietin Analogue Darbepoetin Alpha Persistently Activates Endothelial Akt and Attenuates Progressive Organ Failure Circulation, August 24, 2004; 110(8): 1006 - 1012. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Iimuro, T. Shindo, N. Moriyama, T. Amaki, P. Niu, N. Takeda, H. Iwata, Y. Zhang, A. Ebihara, and R. Nagai Angiogenic Effects of Adrenomedullin in Ischemia and Tumor Growth Circ. Res., August 20, 2004; 95(4): 415 - 423. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. W. Losordo and S. Dimmeler Therapeutic Angiogenesis and Vasculogenesis for Ischemic Disease: Part I: Angiogenic Cytokines Circulation, June 1, 2004; 109(21): 2487 - 2491. [Full Text] [PDF]
|
|
|
|
|
|
R. Kirchmair, R. Gander, M. Egger, A. Hanley, M. Silver, A. Ritsch, T. Murayama, N. Kaneider, W. Sturm, M. Kearny, et al. The Neuropeptide Secretoneurin Acts as a Direct Angiogenic Cytokine In Vitro and In Vivo Circulation, February 17, 2004; 109(6): 777 - 783. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Huang, D. Sun, Z. Wu, C. Yan, M. A. Carroll, H. Jiang, J. R. Falck, and G. Kaley Estrogen Elicits Cytochrome P450--Mediated Flow-Induced Dilation of Arterioles in NO Deficiency: Role of PI3K-Akt Phosphorylation in Genomic Regulation Circ. Res., February 6, 2004; 94(2): 245 - 252. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 C. Heeschen, A. Aicher, R. Lehmann, S. Fichtlscherer, M. Vasa, C. Urbich, C. Mildner-Rihm, H. Martin, A. M. Zeiher, and S. Dimmeler Erythropoietin is a potent physiologic stimulus for endothelial progenitor cell mobilization Blood, August 15, 2003; 102(4): 1340 - 1346. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-S. Silvestre, R. Tamarat, T. G. Ebrahimian, A. Le-Roux, M. Clergue, F. Emmanuel, M. Duriez, B. Schwartz, D. Branellec, and B. I. Levy Vascular Endothelial Growth Factor-B Promotes In Vivo Angiogenesis Circ. Res., July 25, 2003; 93(2): 114 - 123. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Dimmeler and A. M. Zeiher Exercise and Cardiovascular Health: Get Active to "AKTivate" Your Endothelial Nitric Oxide Synthase Circulation, July 1, 2003; 107(25): 3118 - 3120. [Full Text] [PDF]
|
|
|
|
|
|
P. E. Szmitko, P. W.M. Fedak, R. D. Weisel, D. J. Stewart, M. J.B. Kutryk, and S. Verma Endothelial Progenitor Cells: New Hope for a Broken Heart Circulation, June 24, 2003; 107(24): 3093 - 3100. [Full Text] [PDF]
|
|
|
|
 |
|
 X. Peng, S. Haldar, S. Deshpande, K. Irani, and D. A. Kass Wall Stiffness Suppresses Akt/eNOS and Cytoprotection in Pulse-Perfused Endothelium Hypertension, February 1, 2003; 41(2): 378 - 381. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X.-F. Ming, H. Viswambharan, C. Barandier, J. Ruffieux, K. Kaibuchi, S. Rusconi, and Z. Yang Rho GTPase/Rho Kinase Negatively Regulates Endothelial Nitric Oxide Synthase Phosphorylation through the Inhibition of Protein Kinase B/Akt in Human Endothelial Cells Mol. Cell. Biol., December 15, 2002; 22(24): 8467 - 8477. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Kumar, I. Chaudhry, M. B. Reid, and A. M. Boriek Distinct Signaling Pathways Are Activated in Response to Mechanical Stress Applied Axially and Transversely to Skeletal Muscle Fibers J. Biol. Chem., November 22, 2002; 277(48): 46493 - 46503. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Mallat, J.-S. Silvestre, S. Le Ricousse-Roussanne, L. Lecomte-Raclet, A. Corbaz, M. Clergue, M. Duriez, V. Barateau, S. Akira, A. Tedgui, et al. Interleukin-18/Interleukin-18 Binding Protein Signaling Modulates Ischemia-Induced Neovascularization in Mice Hindlimb Circ. Res., September 6, 2002; 91(5): 441 - 448. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
M. Sata and R. Nagai Phosphatidylinositol 3-Kinase: A Key Regulator of Vascular Tone? Circ. Res., August 23, 2002; 91(4): 273 - 275. [Full Text] [PDF]
|
|
|
|
 |
|
 S. Dimmeler and A. M. Zeiher PTEN-uating Restenosis Arterioscler Thromb Vasc Biol, May 1, 2002; 22(5): 715 - 716. [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
L. Vincent, C. Soria, F. Mirshahi, P. Opolon, Z. Mishal, J.-P. Vannier, J. Soria, and L. Hong Cerivastatin, an Inhibitor of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase, Inhibits Endothelial Cell Proliferation Induced by Angiogenic Factors In Vitro and Angiogenesis in In Vivo Models Arterioscler Thromb Vasc Biol, April 1, 2002; 22(4): 623 - 629. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Rossig, A. S. Jadidi, C. Urbich, C. Badorff, A. M. Zeiher, and S. Dimmeler Akt-Dependent Phosphorylation of p21Cip1 Regulates PCNA Binding and Proliferation of Endothelial Cells Mol. Cell. Biol., August 15, 2001; 21(16): 5644 - 5657. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Urbich, D. H. Walter, A. M. Zeiher, and S. Dimmeler Laminar Shear Stress Upregulates Integrin Expression : Role in Endothelial Cell Adhesion and Apoptosis Circ. Res., October 13, 2000; 87(8): 683 - 689. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
F. D. Kolodgie, A. Farb, and R. Virmani Local Delivery of Ceramide for Restenosis : Is There a Future for Lipid Therapy? Circ. Res., August 18, 2000; 87(4): 264 - 267. [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
L. Vincent, C. Soria, F. Mirshahi, P. Opolon, Z. Mishal, J.-P. Vannier, J. Soria, and L. Hong Cerivastatin, an Inhibitor of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase, Inhibits Endothelial Cell Proliferation Induced by Angiogenic Factors In Vitro and Angiogenesis in In Vivo Models Arterioscler Thromb Vasc Biol, April 1, 2002; 22(4): 623 - 629. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|