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 (AT(1))-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 AT(1)-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-1 alpha (SDF-1 alpha) were significantly reduced in BM-Agtr1(-/-) mice, accompanied by a decrease in the serum level of SDF-1 alpha. 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-1 alpha. Conclusions-The BM-AT(1) receptor promotes neointima formation by regulating the mobilization and homing of BM-derived VPCs in a platelet-derived SDF-1 alpha-dependent manner without affecting EPC-mediated reendothelialization. (Arterioscler Thromb Vasc Biol. 2010;30:60-67.)