CCR7-CCL19/CCL21 axis is essential for effective arteriogenesis in a murine model of hindlimb ischemia

Background-In order to identify factors that stimulate arteriogenesis after ischemia, we followed gene expression profiles in two extreme models for collateral artery formation over 28 days after hindlimb ischemia, namely "good-responding" C57BL/6 mice and "poor-responding" BALB/c mice. Methods and Results-Although BALB/c mice show very poor blood flow recovery after ischemia, most known proarteriogenic genes were upregulated more excessively and for a longer period than in C57BL/6 mice. In clear contrast, chemokine genes Ccl19, Ccl21a, and Ccl21c and the chemokine receptor CCR7 were upregulated in C57BL/6 mice 1 day after hindlimb ischemia, but not in BALB/C mice. CCL19 and CCL21 regulate migration and homing of T lymphocytes via CCR7. When subjecting CCR7^-/-/ LDLR^-/- mice to hindlimb ischemia, we observed a 20% reduction in blood flow recovery compared with that in LDLR^-/- mice. Equal numbers of α-smooth muscle actin-positive collateral arteries were found in the adductor muscles of both mouse strains, but collateral diameters were smaller in the CCR7^-/-/LDLR^-/-. Fluorescence-activated cell sorter analyses showed that numbers of CCR7⁺ T lymphocytes (both CD4⁺ and CD8⁺) were decreased in the spleen and increased in the blood at day 1 after hindlimb ischemia in LDLR^-/- mice. At day 1 after hindlimb ischemia, however, numbers of activated CD4⁺ T lymphocytes were decreased in the draining lymph nodes of LDLR^-/- mice compared with CCR7^-/-/LDLR^-/- mice. Conclusions-These data show that CCR7-CCL19/CCL21 axis facilitates retention CD4⁺ T lymphocytes at the site of collateral artery remodeling, which is essential for effective arteriogenesis.