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Akt Takes Center Stage in Angiogenesis Signaling

2000; Lippincott Williams & Wilkins; Volume: 86; Issue: 1 Linguagem: Dinamarquês

10.1161/01.res.86.1.4

1524-4571

Stefanie Dimmeler, Andreas M. Zeiher,

Antiplatelet Therapy and Cardiovascular Diseases

HomeCirculation ResearchVol. 86, No. 1Akt Takes Center Stage in Angiogenesis Signaling Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessEditorialPDF/EPUBAkt Takes Center Stage in Angiogenesis Signaling Stefanie Dimmeler and Andreas M. Zeiher Stefanie DimmelerStefanie Dimmeler From Molecular Cardiology, Department of Internal Medicine IV, University of Frankfurt, Germany. and Andreas M. ZeiherAndreas M. Zeiher From Molecular Cardiology, Department of Internal Medicine IV, University of Frankfurt, Germany. Originally published7 Jan 2000https://doi.org/10.1161/01.RES.86.1.4Circulation Research. 2000;86:4–5The 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.56 Moreover, potent inhibitors of endothelial cell apoptosis such as shear stress or insulin activate Akt.78 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.910 A large body of literature indicates an essential role of endothelial NO for postnatal neovascularization.1112 Most convincingly, eNOS knockout animals are characterized by an impaired angiogenesis in response to ischemia or VEGF administration.12 Mechanistically, Akt stimulation may enhance endothelial NO synthesis and thereby influence the long-term regulation of vessel growth. However, in case of Ang1, this pathway has to be established. Furthermore, additional downstream substrates of Akt may be involved as well (see Figure). The inhibition of the proapoptotic proteins Bad or caspase-9 in addition to the enhanced endothelial NO synthesis, which also inhibits endothelial cell apoptosis, may block apoptosis at several stages in the apoptosis signaling cascade. The question remains what is the importance of the Akt pathway for endothelial cell migration and proliferation, which are prerequisite for angiogenesis. Several in vitro studies indicate that endothelial cell migration also depends on NO.1314 Moreover, recent experiments suggest that at least the VEGF-induced endothelial cell migration requires the activation of Akt.15 Therefore, these studies indeed provide evidence that Akt-dependent NO synthesis contributes to endothelial cell migration. Although there are no data available concerning the mechanism by which Ang1 promotes cell migration, it may turn out that similar pathways are involved. The downstream effector pathways, by which NO mediates its effects, are less clear but may involve integrin-linked signal transduction processes.13Little is known about the involvement of Akt in proliferation. Very recently, Akt was shown to inhibit the Raf-MEK-ERK kinase cascade by Akt-dependent phosphorylation of Raf.1617 This crosstalk between Raf-MEK-ERK and Akt pathways not only switched the biological response of MCF-7 tumor cells from growth arrest to proliferation but also promoted the development of a hypertrophic phenotype in differentiated muscle cells.16 However, Ang1 and VEGF differ with respect to eliciting a proliferative response, although both activate Akt. In contrast to VEGF, which stimulates endothelial cell migration and promotes cell survival and proliferation, Ang1 does not appear to stimulate endothelial cell proliferation.3 If Akt activation is sufficient to induce a proliferative response in endothelial cells, which is a prerequisite for neovascularization, Ang1 should be mitogenic as well. This discrepancy may indicate that endothelial cell growth requires additional signals than Akt alone. Indeed, in the cornea micropocket assay of neovascularization, Ang1 did not promote neovascularization by itself but did promote vascular network maturation, when coadministered with VEGF.18 In line with these studies on postnatal neovascularization are developmental findings showing that, during embryonic development, Ang1 plays a crucial role in mediating reciprocal interactions between the endothelium and surrounding matrix.19 Thus, it appears that Ang1 and VEGF collaborate in angiogenesis to form optimally functional blood vessels, with Ang1 acting rather late to cause maturation and stabilization of vessels subsequent to the earlier angiogenic actions of VEGF. It is conceivable that activation of Akt by Ang1 orchestrates the signaling pathways leading to functional blood vessel formation much like the effects of shear stress exerted by the flow of blood, which is the major determinant of vascular remodeling of preformed blood vessels and also activates Akt in endothelial cells. Importantly, because Ang1 is synthesized in vascular smooth muscle cells,2 it may be ideally suited to act as a paracrine factor to coordinate the interaction between endothelial cells and the surrounding matrix, to influence vascular remodeling processes.Taken together, activation of the Akt kinase orchestrates a number of signaling pathways potentially involved in angiogenesis. The multiple downstream substrates of Akt not only converge to prevent the induction of apoptosis but may also interfere with numerous biological functions of the endothelial monolayer, which contribute to vascular remodeling and vessel integrity during the angiogenic process. However, additional studies are necessary to delineate a causal contribution of Akt in angiogenesis in vivo to establish Akt as a potential useful target for the induction of postnatal neovascularization.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.Download figureDownload PowerPoint Figure 1. Downstream substrates of the protein kinase Akt: potential involvement in apoptosis suppression, endothelial cell migration, and proliferation.FootnotesCorrespondence to Stefanie Dimmeler, PhD, Molecular Cardiology, Department of Internal Medicine IV, University of Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany. E-mail [email protected] References 1 Khwaja A. Akt is more than just a Bad kinase. Nature.1999; 401:33–34.CrossrefMedlineGoogle Scholar2 Kim I, Kim HG, So J-N, Kim JH, Kwak HJ, Koh GY. Angiopoietin-1 regulates endothelial cell survival through the phosphatidylinositol 3′-kinase/Akt signal transduction pathway. Circ Res.2000; 86:24–29.CrossrefMedlineGoogle Scholar3 Davis S, Aldrich TH, Jones PF, Acheson A, Compton DL, Jain V, Ryan TE, Bruno J, Radziejewski C, Maisonpierre PC, Yancopoulos GD. Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloning. Cell.1996; 87:1161–1169.CrossrefMedlineGoogle Scholar4 Kontos CD, Stauffer TP, Yang W-P, York JD, Huang L, Blanar MA, Meyer T, Peters KG. Tyrosine 1101 of Tie2 is the major site of association of p85 and is required for activation of phosphatidylinositol 3-kinase and Akt. Mol Cell Biol.1998; 178:4131–4140.Google Scholar5 Gerber HP, McMurtrey A, Kowalski J, Yan M, Keyt BA, Dixit V, Ferrara N. Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3′-kinase/Akt signal transduction pathway. Requirement for Flk-1/KDR activation. J Biol Chem.1998; 273:30336–30343.CrossrefMedlineGoogle Scholar6 Fujio Y, Walsh K. Akt mediates cytoprotection of endothelial cells by vascular endothelial growth factor in an anchorage-dependent manner. J Biol Chem.1999; 274:16349–16354.CrossrefMedlineGoogle Scholar7 Dimmeler S, Assmus B, Hermann C, Haendeler J, Zeiher AM. Fluid shear stress stimulates phosphorylation of Akt in human endothelial cells: involvement in suppression of apoptosis. Circ Res.1998; 83:334–341.CrossrefMedlineGoogle Scholar8 Hermann C, Assmus B, Urbich C, Zeiher AM, Dimmeler S. Insulin-mediated stimulation of protein kinase Akt: a potent survival signaling cascade for endothelial cells. Arterioscler Thromb Vasc Biol. In press.Google Scholar9 Dimmeler S, Fisslthaler B, Fleming I, Hermann C, Busse R, Zeiher AM. Activation of nitric oxide synthase in endothelial cells via Akt-dependent phosphorylation. Nature.1999; 399:601–605.CrossrefMedlineGoogle Scholar10 Fulton D, Gratton JP, McCabe TJ, Fontana J, Fujio Y, Walsh K, Franke TF, Papapetropoulos A, Sessa WC. Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature.1999; 399:597–601.CrossrefMedlineGoogle Scholar11 Papapetropoulos A, Garcia-Cardena G, Madri JA, Sessa WC. Nitric oxide production contributes to the angiogenic properties of vascular endothelial growth factor in human endothelial cells. J Clin Invest.1997; 100:3131–3139.CrossrefMedlineGoogle Scholar12 Murohara T, Asahara T, Silver M, Bauters C, Masuda H, Kalka C, Kearney M, Chen D, Symes JF, Fishman MC, Huang PL, Isner JM. Nitric oxide synthase modulates angiogenesis in response to tissue ischemia. J Clin Invest.1998; 101:2567–2578.CrossrefMedlineGoogle Scholar13 Murohara T, Witzenbichler B, Spyridopoulos I, Asahara T, Ding B, Sullivan A, Losordo DW, Isner JM. Role of endothelial nitric oxide synthase in endothelial cell migration. Arterioscler Thromb Vasc Biol.1999; 19:1156–1161.CrossrefMedlineGoogle Scholar14 Noiri E, Lee E, Testa J, Quigley J, Colflesh D, Keese CR, Giaever I, Goligorsky MS. Podokinesis in endothelial cell migration: role of nitric oxide. Am J Physiol.1998; 274:C236–C244.CrossrefMedlineGoogle Scholar15 Dimmeler S, Urbich C, Zeiher AM. Vascular endothelial growth factor-induced endothelial cell migration requires Akt-stimulated activation of endothelial nitric oxide-synthase. Circulation. 1999;100(suppl I):I-483. Abstract 2543.Google Scholar16 Zimmermann S, Moelling K. Phosphorylation and regulation of Raf by Akt (protein kinase B). Science.1999; 286:1741–1744.CrossrefMedlineGoogle Scholar17 Rommel C, Clarke BA, Zimmermann S, Nunez L, Rossmann R, Reid K, Moelling K, Yancopoulos GD, Glass DJ. Differentiation stage-specific inhibition of the Raf-MEK-ERK pathway by Akt. Science.1999; 286:1738–1741.CrossrefMedlineGoogle Scholar18 Asahara T, Chen D, Takahashi T, Fujikawa K, Kearney M, Magner M, Yancopoulos GD, Isner JM. Tie2 receptor ligands, angiopoietin-1 and angiopoietin-2, modulate VEGF-induced postnatal neovascularization. Circ Res.1998; 83:233–240.CrossrefMedlineGoogle Scholar19 Suri C, Jones PF, Patan S, Bartunkova S, Maisonpierre PC, Davis S, Sato TN, Yancopoulos GD. Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell.1996; 87:1171–1180.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails January 7, 2000Vol 86, Issue 1Article InformationMetrics Download: 342 © 2000 American Heart Association, Inc.https://doi.org/10.1161/01.RES.86.1.4 Originally publishedJanuary 7, 2000 Keywordsvascular endothelial growth factornitric oxideangiopoietinprotein kinase BapoptosisPDF download