Integrin-linked kinase regulates endothelial cell survival and vascular development

Erik B. Friedrich, Emerson Liu, Sumita Sinha, Stuart Cook, David S. Milstone, Calum A. MacRae, Massimo Mariotti, Peter J. Kuhlencordt, Thomas Force, Anthony Rosenzweig, Rene St-Arnaud, Shoukat Dedhar, Robert E. Gerszten

Research output: Contribution to journalArticlepeer-review

Abstract

Integrin-linked kinase (ILK) is a phosphoinositide 3-kinase-dependent serine/threonine kinase that interacts with β 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 β1 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.

Original languageEnglish
Pages (from-to)8134-8144
Number of pages11
JournalMolecular and Cellular Biology
Volume24
Issue number18
DOIs
Publication statusPublished - Sep 2004

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

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