© 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{at}em.uni-frankfurt.de
Key Words: protein kinase B • angiopoietin • vascular endothelial growth factor • nitric oxide • apoptosis
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Introduction |
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 Top Introduction References |
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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 an
essential role of endothelial NO for postnatal
neovascularization.11 12 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.13 14 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.13
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Little 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.16 17 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.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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