Abstract 16330: Chemokines CCL19 and CCL21 Contribute to Homing and Retention of T-Lymphocytes during Arteriogenesis via the Chemokine Receptor CCR7
In search of factors that can stimulate arteriogenesis in a clinical setting, we followed gene expression profiles in two extreme models for collateral artery formation over 28 after hind limb ischemia (HLI) via ligation of the femoral artery, namely ‘good responding’ C57Bl/6 mice and ‘poor responding’ BALB/c mice. Although BALB/c mice show very poor blood flow recovery after ischemia, most known pro-arteriogenic genes, including many inflammatory pathways, were upregulated more excessively and for a longer period of time than in C57BL/6 mice. In clear contrast, 2 important cytokines, CCL19 and CCL21 were upregulated in C57BL/6 1 day after HLI, but not at all in BALB/C. Via their joint receptor CCR7, CCL19 and CCL21 regulate migration and homing of both dendritic cells and T-lymphocytes, of which the latter play a known role in arteriogenesis. When subjecting CCR7-/-/LDLR-/- mice to HLI, we observed a 20% reduction in blood flow recovery compared to LDLR-/- mice (on regular chow diet). Equal numbers of α-SMA positive collateral arteries were counted in the adductor muscles of both mouse strains, but diameters were smaller in the CCR7-/-/LDLR-/- than in the LDLR-/- mice. FACS analyses showed that numbers of CCR7+ T-lymphocytes (both CD4+ and CD8+) were increased in the blood and draining lymph nodes at day 1 after HLI in LDLR-/- mice. Also, more CCR7+ cells were counted in the adductor muscle, the site of remodeling collateral arteries, 1 day after HLI in these mice (p=0.07). Also at day 1 after HLI however, numbers of in particular CD4+ T-lymphocytes were higher in both draining and non-draining lymph nodes of CCR7-/-/LDLR-/- mice than in LDLR-/- mice. These data imply that CCR7 is involved in homing of CD4+ T-lymphocytes to the adductor muscle, but also in their retention at the site of collateral artery remodeling during arteriogenesis. In conclusion, CCR7 plays an important role in arteriogenesis via homing and retention of in particular CD4+ T cells. CCR7 deficiency leads to hampered blood flow recovery after ischemia. Acting on their joint receptor CCR7, cytokines CCL19 and CCL21 may provide interesting new tools in therapeutic arteriogenesis.
- © 2012 by American Heart Association, Inc.