Article

Akt1 regulates pathological angiogenesis, vascular maturation and permeability in vivo.

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.
Nature Medicine (impact factor: 22.46). 12/2005; 11(11):1188-96. DOI:10.1038/nm1307 pp.1188-96
Source: PubMed

ABSTRACT 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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Keywords

Akt-thrombospondin axis
 
angiogenesis-dependent pathologies
 
angiogenic abnormalities
 
Angiogenic responses
 
blood vessel maturation
 
crucial role
 
endogenous vascular regulators
 
endothelial nitric oxide synthase
 
enhanced responses
 
eNOS
 
major phenotypic changes
 
precise roles
 
predominant isoform
 
proliferation
 
TSP-1
 
vascular cells
 
vascular integrity
 
vascular maturation
 
vascular permeability
 
wild-type bone marrow
 

Juhua Chen