Abstract 12382: Endothelial Specific Inhibition of NF-kappa B Results in Reduced Vessel Maturation Due to Poor Monocyte Recruitment and Impaired Notch and PDGF Signaling
Background: Arteriogenesis plays an important role in effective restoration of blood flow in ischemic tissue. The primary signal behind the induction of vessel growth is thought to be endothelial cell-dependent recruitment of blood -derived mononuclear cells due to shear-stress-dependent activation of nuclear factor (NF) κB. We used inducible transgenic mouse model to selectively inhibit NFkB signaling in endothelial cells and to examine the effect of this manipulation on the vessel growth.
Methods: We employed a double-transgenic approach using a Tet-OFF system to express IkBα super-repressor mutant (NFkB-DN) specific in endothelium under Tie-2 and VE-Cadherin promoter. The vessel growth was examined in retinal and hindlimb ischemia model. The extent of vessel growth following femoral artery ligation was assessed by micro CT and distal limb perfusion was measured by laser-Doppler imaging (LDI).
Results: Following femoral artery ligation serial LDI showed significantly reduced blood flow restoration in NFkB-DN mice compared to control mice (day 21: 0.26 vs. 0.83, n=4 mice/group, p<0.05). Three days after femoral artery ligation there was reduced recruitment of CD45+ leukocytes in NFB-DN mice. This was followed at day 7 post-ligation by reduced mural cell recruitment, lower PDGF-BB expression and altered Notch signaling. Jagged1 was increased and Dll4 decreased in NFkB-DN as compared to control mice. At day 21 quantitative micro CT analysis of NFB-DN mice showed a dense disorganized arteriolar vessel network (≤ 40 μm vessel diameters). Examination of the retinal vasculature in NFkB-DN mice model demonstrated poor mural cell coverage and increased branching in capillary plexus.
Conclusion: These data suggest that endothelial specific inhibition of NFkB signaling pathway results in reduced leukocyte recruitment in ischemic hindlimb and formation of disorganized vessel network due to impaired Notch signaling and PDGF-dependent vessel maturation.
- © 2010 by American Heart Association, Inc.