Bone Marrow AT1 Augments Neointima Formation by Promoting Mobilization of Smooth Muscle Progenitors via Platelet-Derived SDF-1α

Objectives— Bone marrow (BM)-derived endothelial progenitor cells (EPCs) and vascular smooth muscle progenitor cells (VPCs) contribute to neointima formation, whereas the angiotensin II (Ang II) type 1 receptor (AT1)-mediated action on BM-derived progenitors remains undefined. Methods and Results— A wire-induced vascular injury was performed in the femoral artery of BM-chimeric mice whose BM was repopulated with AT1-deficient (BM-Agtr1−/−) or wild-type (BM-Agtr1+/+) cells. Neointima formation was profoundly reduced by 38% in BM-Agtr1−/− mice. Although the number of circulating EPCs (Sca-1+Flk-1+) and extent of reendothelialization did not differ between the 2 groups, the numbers of both circulating VPCs (c-Kit−Sca-1+Lin−) and tissue VPCs (Sca-1+CD31−) incorporated into neointima were markedly decreased in BM-Agtr1−/− mice. The accumulation of aggregated platelets and their content of stromal cell–derived factor-1α (SDF-1α) were significantly reduced in BM-Agtr1−/− mice, accompanied by a decrease in the serum level of SDF-1α. Thrombin-induced platelets aggregation was dose-dependently inhibited (45% at 0.1 IU/mL, P <0.05) in Agtr1−/− platelets compared with Agtr1+/+ platelets, accompanied by the reduced expression and release of SDF-1α. Conclusions— The BM-AT1 receptor promotes neointima formation by regulating the mobilization and homing of BM-derived VPCs in a platelet-derived SDF-1α–dependent manner without affecting EPC-mediated reendothelialization.