Bone marrow at1 augments neointima formation by promoting mobilization of smooth muscle progenitors via platelet-derived sdf-1α

Abstract

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-1Flk-1) and extent of reendothelialization did not differ between the 2 groups, the numbers of both circulating VPCs (c-KitSca-1Lin) and tissue VPCs (Sca-1CD31) 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. © 2010 American Heart Association, Inc.