Abstract 3956: CD11b Positive Monocytes Are Required for Endothelial Regeneration
Bone marrow (BM)-derived circulating endothelial progenitor cells (EPC) contribute to endothelial cell (EC) regeneration. Systemic transfusion of EPC fosters the restoration of the endothelium after EC damage in mice. Transfusion of mononuclear cells (MNC) leads to an even more pronounced endothelial regeneration compared to EPCs. Here, we determine the role of monocytic cells and their interaction with circulating EPC on EC regeneration. To evaluate the effect of monocytes on re-endothelialization, neointima formation, and endothelial function, wild-type (WT) mice received repetitive intravenous injections of spleen-derived MNC, CD11b-depleted MNC, CD11b+ monocytes, or cell-free vehicle after EC denudation. Endothelial restoration was enhanced and neointima formation reduced after transfusion of MNC and CD11b+ cells. CD11b-depleted cells had no effect. Transfusion of CD11b+ cells in ApoE−/− mice improved endothelial-dependent vasorelaxation while CD11b-depleted cells had no effect. Next, WT mice were treated with clodronate liposomes (10μl/g bw) which induces the ablation of circulating monocytes. Re-endothelialization was diminished in clodronate- compared to vehicle-treated mice. Next, we selectively depleted CD11b+ monocytes using CD11b-DTR mice which express the human diphtheria toxin receptor (DTR) under the control of the CD11b promoter. Treatment with diphtheria toxin (DT) resulted in the complete ablation of circulating monocytes. Re-endothelialization was delayed in DT-treated compared to vehicle-treated mice. Systemic treatment of WT mice with Sca1+ EPC improves endothelial function. Repetitive transfusion of Sca1+ cells enhanced re-endothelialization in vehicle-treated CD11b-DTR mice compared to DT-treated mice. Rescue experiments showed that transfusion of CD11b+ cells in CD11b-DTR mice treated with either vehicle or DT resulted in a comparable enhancement of re-endothelialization. Our results indicate that circulating CD11b+ monocytes contribute to EC regeneration. Ablation of monocytes in vivo leads to a delay in re-endothelialization after focal EC damage which can not be rescued by transfusion of Sca1+ cells.