Nature Medicine 11, 1188 - 1196 (2005)
Published online: 16 October 2005; | doi:10.1038/nm1307
Akt1 regulates pathological angiogenesis, vascular maturation and permeability in vivoJuhua Chen1, 4, Payaningal R Somanath1, 4, Olga Razorenova1, William S Chen2, Nissim Hay2, Paul Bornstein3
& Tatiana V Byzova11
Department of Molecular Cardiology, Joseph J. Jacobs Center for Thrombosis and Vascular Biology, NB50, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA. 2
Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, 900 South Ashland Avenue, Chicago, Illinois 60607, USA. 3
Department of Biochemistry, Box 357350, University of Washington, Seattle, Washington 98195, USA. 4
These authors contributed equally to this work.
Correspondence should be addressed to Tatiana V Byzova byzovat@ccf.org Akt kinases control essential cellular functions, including proliferation, apoptosis, metabolism and transcription, and have been proposed as promising targets for treatment of angiogenesis-dependent pathologies, such as cancer and ischemic injury. But their precise roles in neovascularization remain elusive. Here we show that Akt1 is the predominant isoform in vascular cells and describe the unexpected consequences of Akt1 knockout on vascular integrity and pathological angiogenesis. Angiogenic responses in three distinct in vivo models were enhanced in Akt1-/- mice; these enhanced responses were associated with impairment of blood vessel maturation and increased vascular permeability. Although impaired vascular maturation in Akt1-/- mice may be attributed to reduced activation of endothelial nitric oxide synthase (eNOS), the major phenotypic changes in vascular permeability and angiogenesis were linked to reduced expression of two endogenous vascular regulators, thrombospondins 1 (TSP-1) and 2 (TSP-2). Re-expression of TSP-1 and TSP-2 in mice transplanted with wild-type bone marrow corrected the angiogenic abnormalities in Akt1-/- mice. These findings establish a crucial role of an Akt-thrombospondin axis in angiogenesis.
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