Akt1/protein kinase Bα is critical for ischemic and VEGF-mediated angiogenesis
Eric Ackah, … , Kenneth Walsh, William C. Sessa
Eric Ackah, … , Kenneth Walsh, William C. Sessa
Published August 1, 2005
Citation Information: J Clin Invest. 2005;115(8):2119-2127. https://doi.org/10.1172/JCI24726.
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Research Article Vascular biology

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

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.

Authors

Eric Ackah, Jun Yu, Stefan Zoellner, Yasuko Iwakiri, Carsten Skurk, Rei Shibata, Noriyuki Ouchi, Rachael M. Easton, Gennaro Galasso, Morris J. Birnbaum, Kenneth Walsh, William C. Sessa

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Ischemia-stimulated EPC mobilization is impaired in Akt1–/– mice; admini...
Ischemia-stimulated EPC mobilization is impaired in Akt1–/– mice; administration of Akt1–/– EPCs does not improve perfusion of ischemic limbs. (A) Representative photomicrographs showing Ac-Dil-LDL–positive EPCs isolated from peripheral blood mononuclear cells of WT and Akt1–/– mice after femoral ligation. Magnification, ×200. (B) For each animal, Ac-Dil-LDL–positive cells in 10 low-power (×100) fields were counted. EPC counts were obtained at baseline and 6 days after induction of limb ischemia; n = 3–6. (C) Representative laser Doppler blood flow images of the limbs of WT mice at postoperative day 14 after femoral ligation and intravenous administration of medium, WT EPCs, or Akt1–/– EPCs (see Methods). (D) Quantitative analysis of laser Doppler blood flow images. Data are expressed as a ratio of the left (ischemic) to right (control) limb perfusion; n = 4. **P < 0.01.