Abstract 5446: Impaired Neoangiogenesis in S100A1-deficient Mice is Rescued by Bone Marrow Transplantation
Recent data from our lab have demonstrated the importance of S100A1, a small EF-hand, Ca handling protein in endothelial cell NO homeostasis, which is critical for the neoangiogenic response to ischemia. Thus in this study we examined the role of S100A1 in the neoangiogenic response to limb ischemia. Relative to congenic C57Bl/6 (WT) control mice, femoral artery resection (FAR) in 12 week-old S100A1 ko (SKO) mice led to a decrease in blood flow recovery in the ischemic limb (by 50%+/−6% within 14 days) an increase in tissue necrosis and a high incidence of limb auto-amputation (0/22 for WT vs 10/18 for SKO, p<0.01, Fisher’s exact test). Compared to WT (n-13) mice, FAR in SKO (n=8) mice lead to a decrease in VEGF mRNA and protein expression (by 48%, p<0.05, T-test) in the ischemic limb as well as an increase in the expression of inflammatory and anti-angiogenic markers (TNF (2.2-fold), IL-1b, (7-fold), IL-6 (10-fold), TSP-1 (2-fold), iNOS (2.2-fold)). In accord with the phenotype, ECs isolated from SKO mice are compromised in tube formation on matrigel matrix, show a decrease in VEGF mRNA and protein expression (by 50%) and demonstrate an increased expression of the cell adhesion proteins ICAM and VCAM (by 2-fold) under basal conditions. Transplantation of WT, but not SKO bone marrow into SKO mice 4 weeks before FAR restored the increase in VEGF levels following FAR and prevented the limb necrosis and auto-amputation, possibly by providing WT EC progenitor cells (EPC) to the ischemic hind limb. Our data suggest that S100A1 expression in either the ECs of the ischemic tissue or the bone marrow derived EPC is essential for the neoangiogenic response to ischemia and further studies are warranted to determine whether loss of S100A1 expression is involved in the pathogenesis of peripheral arterial disease and supply of S100A1 might be of therapeutic benefit.