Cathelicidin, NFKB regulate angiogenesis
Kofi
NF kappaB Activation in Embryonic Endothelial Progenitor Cells Enhances
Neovascularization Via PSGL-1 Mediated Recruitment: Novel Role for LL37.
Pfosser A, El-Aouni C, Pfisterer I, Dietz M, Globisch F, Stachel G,
Trenkwalder T, Pinkenburg O, Horstkotte J, Hinkel R, Sperandio M,
Hatzopoulos AK, Boekstegers P, Bals R, Kupatt C.
Medizinische Klinik I, Klinikum Grosshadern,
Ludwig-Maximilians-University Munich, Germany.
Embryonal (e)EPCs are capable of inducing therapeutic angiogenesis in a
chronic hindlimb model. However, the proportion of eEPCs recruited to
the ischemic tissue appears to be a limiting step for the induction of
cell-based therapeutic neovascularization. In the present study, we
primed eEPCs with the human cathelicidin LL37 (hCAP-18) ex vivo to
selectively enhance the eEPC-dependent gain of perfusion in vivo and
elucidated the mechanism of action of LL37 on eEPCs.Methods: 7 days
after femoral artery excision, 5x10(6) eEPCs (wild type=wt, transiently
p65 transient=p65t, stable p65 transfected=p65s, LL37 peptide
preincubated=LL37-eEPCs) were retroinfused into the anterior tibial
vein. Recruitment of diI-labeled eEPCs in the ischemic gastrocnemic (GC)
muscle was investigated 2d later, whereas collateral growth and
perfusion score (obtained by fluorescent microspheres) were assessed at
d7 and d35 and are given as % of d7 level. Capillary/muscle fiber ratio
(C/MF) in the ischemic lower limb was obtained at d35.Results: Embryonic
EPC recruitment in vitro and in vivo was found elevated after LL37 and
p65t pretreatment, but not in p65s-eEPCs displaying increased
IkappaBalpha or after LL37 in IkappaB-DN overexpressing eEPCs. Using
LL37- and p65t-eEPCs, collateral growth (181+/-10% and 165+/-8%,
respectively) surpassed that of wt-eEPCs (135+/-7%), increasing
perfusion ratio (208+/-20% and 210+/-17% vs. 142+/-12% in wt-eEPCs,
respectively), whereas p65s-eEPCs exerted no additive effect (collateral
growth 130+/- 8%; perfusion ratio 155+/-15%). Moreover,
p65t-eEPC-induced neovascularization was abrogated by blocking
antibodies against E-selectin and PSGL-1.We conclude that NF kappaB
activation by LL37 or transient p65-transfection increases functionally
relevant eEPC recruitment to ischemic muscle tissue via induction of
PSGL-1 and E-selectin.
PMID: 20014279