Caspase-8 is involved in neovascularization-promoting progenitor cell functions.
OBJECTIVE
Endothelial progenitor cells (EPCs) comprise a heterogeneous population of cells, which improve therapeutic neovascularization after ischemia. The neovascularization-promoting potential of progenitor cells depends on survival and retention of the infused cells to the tissue. Caspases mediate apoptosis but are also involved in other critical biological processes. Therefore, we aimed to address the role of caspases in proangiogenic cells.


RESULTS
The caspase-8 inhibitor zIETD abrogated the ex vivo formation of EPCs, inhibited EPC adhesion and migration, and reduced their capacity to improve neovascularization in vivo. Consistently, cells isolated from caspase-8-deficient mice exhibited a reduced capacity for enhancing neovascularization when transplanted into mice after hindlimb ischemia. Because inhibition of Caspase-8 reduced the adhesion and homing functions of EPCs, we further determined the surface expression of integrins and receptors involved in cell recruitment to ischemic tissues. Pharmacological inhibition of caspase-8 and genetic depletion of caspase-8 reduced the expression of the fibronectin receptor subunits alpha5 and beta1 and the SDF-1 receptor CXCR4. Moreover, we identified the E3 ubiquitin ligase Cbl-b, which negatively regulates integrin and receptor-mediated signaling, as a potential Caspase-8 substrate.


CONCLUSIONS
In summary, our data demonstrate a novel apoptosis-unrelated role of caspase-8 in proangiogenic cells.
Scharner
Dörte
D
Department of Internal Medicine III, University of Frankfurt, Frankfurt, Germany.
Rössig
Lothar
L
Carmona
Guillaume
G
Chavakis
Emmanouil
E
Urbich
Carmen
C
Fischer
Ariane
A
Kang
Tae-Bong
TB
Wallach
David
D
Chiang
Yungping Jeffrey
YJ
Deribe
Yonathan Lissanu
YL
Dikic
Ivan
I
Zeiher
Andreas M
AM
Dimmeler
Stefanie
S
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D056769:Alstrom Syndrome; D000818:Animals; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism*; D061945:Caspase Inhibitors; D002448:Cell Adhesion; D002465:Cell Movement; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology* / Q000637:transplantation; D006614:Hindlimb; D006801:Humans; D039564:Integrin alphaV / Q000378:metabolism; D019012:Integrin beta1 / Q000378:metabolism; D007511:Ischemia / Q000201:enzymology* / Q000503:physiopathology / Q000601:surgery; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D018482:Muscle, Skeletal / Q000098:blood supply*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D009842:Oligopeptides / Q000494:pharmacology; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D017469:Receptors, Fibronectin / Q000378:metabolism; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000187:drug effects / Q000201:enzymology*
D048868:Adaptor Proteins, Signal Transducing; C527276:CXCR4 protein, human; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D039564:Integrin alphaV; D019012:Integrin beta1; D009842:Oligopeptides; D012333:RNA, Messenger; D019718:Receptors, CXCR4; D017469:Receptors, Fibronectin; C403753:benzyloxycarbonyl-isoleucyl-glutamyl-threonyl-aspartic acid fluoromethyl ketone; C492211:CBLB protein, human; D050721:Proto-Oncogene Proteins c-cbl; C505530:CASP8 protein, human; C505526:Casp8 protein, mouse; D053181:Caspase 8