Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 115, Issue 8, Pages 2119-2127Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI24726
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Funding
- NHLBI NIH HHS [P01 HL 70295, P01 HL070295, R01 HL057665, R01 HL064793, R01 HL061371, R01 HL 64793, R01 HL 57665, R01 HL 61371] Funding Source: Medline
- NIGMS NIH HHS [GM07205, T32 GM007205] Funding Source: Medline
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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.
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