Background-T lymphocytes, components of the immune and inflammatory systems, are involved in such normal processes as wound healing and host defense against infection and in such pathological processes as tumor growth and atherosclerotic plaque development. Angiogenesis is a mechanism common to each. Because CD4ϩ T lymphocytes are active in regulating humoral and cellular responses of the immune system, we determined whether CD4ϩ cells contribute to collateral vessel development by using the mouse ischemic hindlimb model. Methods and Results-One week after ischemia, CD4Ϫ/Ϫ mice showed reduced collateral flow induction, macrophage number, and vascular endothelial growth factor levels in the ischemic muscle compared with wild-type mice. There was also delayed recovery of hindlimb function and increased muscle atrophy/fibrosis. Spleen-derived purified CD4ϩ T cells infused into CD4Ϫ/Ϫ mice selectively localized to the ischemic limb and significantly increased collateral flow as well as macrophage number and vascular endothelial growth factor levels in the ischemic muscle. Muscle function and damage also improved. Conclusions-These results indicate an important role of CD4ϩ cells in collateral development, as demonstrated by a 25%decrease in blood flow recovery after femoral artery ligation. Our data also suggest that CD4ϩ T cells control the arteriogenic response to acute hindlimb ischemia, at least in part, by recruiting macrophages to the site of active collateral artery formation, which in turn triggers the development of collaterals through the synthesis of arteriogenic cytokines.

Background-Previous studies have demonstrated that macrophages and CD4ϩ T lymphocytes play pivotal roles in collateral development. Indirect evidence suggests that CD8 ϩ T cells also play a role. Ϫ/Ϫ mice immediately after femoral artery ligation, they selectively homed to the ischemic hind limb but were unable to recruit CD4 ϩ mononuclear cells and did not improve blood flow recovery. Conclusions-These results demonstrate that CD8ϩ T cells importantly contribute to the early phase of collateral development. After femoral artery ligation, CD8 ϩ T cells infiltrate the site of collateral vessel growth and recruit CD4 ϩ mononuclear cells through the expression of IL-16. Our study provides further evidence of the significant role of the immune system in modulating collateral development in response to peripheral ischemia. (Circulation. 2006;113:118-124.)