Home LiteratureArticle Details
PMID: 16075056 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, U.S. Gov't, P.H.S.

Akt1/protein kinase Balpha is critical for ischemic and VEGF-mediated angiogenesis.

The Journal of clinical investigation ·Vol. 115 ·No. 8 ·2005-08-00 ·Pages 2119-27

Ackah E, Yu J, Zoellner S, Iwakiri Y, Skurk C, Shibata R, Ouchi N, Easton RM, Galasso G, Birnbaum MJ, Walsh K, Sessa WC

Abstract

Akt, or protein kinase B, is a multifunctional serine-threonine protein kinase implicated in a diverse range of cellular functions including cell metabolism, survival, migration, and gene expression. However, the in vivo roles and effectors of individual Akt isoforms in signaling are not explicitly clear. Here we show that the genetic loss of Akt1, but not Akt2, in mice results in defective ischemia and VEGF-induced angiogenesis as well as severe peripheral vascular disease. Akt1 knockout (Akt1-/-) mice also have reduced endothelial progenitor cell (EPC) mobilization in response to ischemia, and reintroduction of WT EPCs, but not EPCs isolated from Akt1-/- mice, into WT mice improves limb blood flow after ischemia. Mechanistically, the loss of Akt1 reduces the basal phosphorylation of several Akt substrates, the migration of fibroblasts and ECs, and NO release. Reconstitution of Akt1-/- ECs with Akt1 rescues the defects in substrate phosphorylation, cell migration, and NO release. Thus, the Akt1 isoform exerts an essential role in blood flow control, cellular migration, and NO synthesis during postnatal angiogenesis.

MeSH Terms
Animals Blood Flow Velocity Cell Movement/genetics Endothelium, Vascular/enzymology,pathology Fibroblasts/enzymology,pathology Hindlimb/blood supply,enzymology,pathology Humans Ischemia/enzymology,genetics,pathology Mice Mice, Knockout Neovascularization, Pathologic/enzymology,genetics Nitric Oxide/biosynthesis Protein Serine-Threonine Kinases/genetics,metabolism Proto-Oncogene Proteins/genetics,metabolism Proto-Oncogene Proteins c-akt
Chemicals
Proto-Oncogene Proteins Nitric Oxide AKT1 protein, human AKT2 protein, human Akt2 protein, mouse Protein Serine-Threonine Kinases Proto-Oncogene Proteins c-akt
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Ackah Eric
Department of Pharmacology and Program in Vascular Cell Signaling and Therapeutics, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, Connecticut 06536-0812, USA.
Yu Jun
Zoellner Stefan
Iwakiri Yasuko
Skurk Carsten
Shibata Rei
Ouchi Noriyuki
Easton Rachael M
Galasso Gennaro
Birnbaum Morris J
Walsh Kenneth
Sessa William C
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI24726
Published
2005-08-00
Pages
2119-27
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC1180542
Subset
IM
Grants
NHLBI NIH HHS · P01 HL070295 · United States
NHLBI NIH HHS · R01 HL 61371 · United States
NIGMS NIH HHS · GM07205 · United States
NHLBI NIH HHS · R01 HL064793 · United States
NHLBI NIH HHS · R01 HL057665 · United States
NIGMS NIH HHS · T32 GM007205 · United States
NHLBI NIH HHS · R01 HL 57665 · United States
NHLBI NIH HHS · R01 HL 64793 · United States
NHLBI NIH HHS · P01 HL 70295 · United States
NHLBI NIH HHS · R01 HL061371 · United States
Corrections
CommentIn
PMID: 16075047
External Links
PubMed source DOI: 10.1172/JCI24726 PMC Full Text View journal details
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