Integrin-linked kinase regulates endothelial cell survival and vascular development.
Integrin-linked kinase (ILK) is a phosphoinositide 3-kinase-dependent serine/threonine kinase that interacts with beta 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 beta1 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.
Friedrich
Erik B
EB
Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital East-8307, 149 13th St., Charlestown, MA 02129, USA.
Liu
Emerson
E
Sinha
Sumita
S
Cook
Stuart
S
Milstone
David S
DS
MacRae
Calum A
CA
Mariotti
Massimo
M
Kuhlencordt
Peter J
PJ
Force
Thomas
T
Rosenzweig
Anthony
A
St-Arnaud
Rene
R
Dedhar
Shoukat
S
Gerszten
Robert E
RE
D000818:Animals; D030801:Animals, Genetically Modified; D001483:Base Sequence; D002470:Cell Survival; D002478:Cells, Cultured; D018076:DNA, Complementary / Q000235:genetics; D004730:Endothelium, Vascular / Q000166:cytology* / Q000196:embryology / Q000201:enzymology*; D005260:Female; D017353:Gene Deletion; D051379:Mice; D008822:Mice, Transgenic; D011247:Pregnancy; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D000099200:Scaffold Protein ILK
D018076:DNA, Complementary; D017346:Protein Serine-Threonine Kinases; D000099200:Scaffold Protein ILK