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Molecular and Cellular Biology, September 2004, p. 8134-8144, Vol. 24, No. 18
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.18.8134-8144.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Integrin-Linked Kinase Regulates Endothelial Cell Survival and Vascular Development

Erik B. Friedrich,^1, Emerson Liu,^1, Sumita Sinha,¹ Stuart Cook,² David S. Milstone,³ Calum A. MacRae,² Massimo Mariotti,² Peter J. Kuhlencordt,⁴ Thomas Force,⁵ Anthony Rosenzweig,² Rene St-Arnaud,⁶ Shoukat Dedhar,⁷ and Robert E. Gerszten^1,2*

Center for Immunology and Inflammatory Diseases,¹ Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, and Harvard Medical School, Boston,² Vascular Research Division, Department of Pathology, Brigham and Women's Hospital,³ Molecular Cardiology Research Institute, New England Medical Center, Tufts University School of Medicine, Boston, Massachusetts,⁵ Department of Medicine, Julius-Maximilians-Universität, Würzburg, Germany,⁴ Shriners Hospital and McGill University, Montreal, Quebec, Canada,⁶ Department of Biochemistry and Molecular Biology, University of British Columbia, and BC Cancer Agency, Jack Bell Research Centre at Vancouver General Hospital and Health Service Center, Vancouver, British Columbia, Canada⁷

Received 18 February 2004/ Returned for modification 28 March 2004/ Accepted 30 May 2004

Integrin-linked kinase (ILK) is a phosphoinositide 3-kinase-dependent serine/threonine kinase that interacts with ß integrins. Here we show that endothelial cell (EC)-specific deletion of ILK in mice confers placental insufficiency with decreased labyrinthine vascularization, yielding no viable offspring. Deletion of ILK in zebra fish using antisense morpholino oligonucleotides results in marked patterning abnormalities of the vasculature and is similarly lethal. To dissect potential mechanisms responsible for these phenotypes, we performed ex vivo deletion of ILK from purified EC of adult mice. We observed downregulation of the active-conformation of ß1 integrins with a striking increase in EC apoptosis associated with activation of caspase 9. There was also reduced phosphorylation of the ILK kinase substrate, Akt. However, phenotypic rescue of ILK-deficient EC by wild-type ILK, but not by a constitutively active mutant of Akt, suggests regulation of EC survival by ILK in an Akt-independent manner. Thus, endothelial ILK plays a critical role in vascular development through integrin-matrix interactions and EC survival. These data have important implications for both physiological and pathological angiogenesis.

E.B.F. and E.L. contributed equally to this work.

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