Abstract 3939: Bone Marrow AT1 Receptor Augments Neointima Formation by Promoting Mobilization of Smooth Muscle Progenitor Cells in Platelet-Derived SDF-1α-Dependent Manner
[BACKGROUND] Bone marrow (BM)-derived endothelial progenitor cells (EPCs) and vascular smooth muscle progenitor cells (VPCs) contribute to neointima formation, whereas angiotensin II type 1 receptor (AT1)-mediated mobilization/homing kinetics of BM-derived progenitor cells after vascular injury remains poorly defined.
[METHOD AND RESULT] Vascular injury was performed by inserting a spring-wire into the femoral artery of BM-chimeric mice whose BM was repopulated with AT1-deficient cells (BM-Agtr1−/−) or wild type cells (BM-Agtr1+/+). Neointimal formation was profoundly reduced by 38% in BM-Agtr1−/− (P<0.05). Although the circulating EPCs (Flk-1+Sca-1+) and the extent of reendothelialization did not differ between the BM-Agtr1−/− and BM-Agtr1+/+ mice, circulating VPCs (c-Kit−Sca-1+Lin−) and Sca-1+CD31−cells which were incorporated into neointima were markedly decreased in BM-Agtr1−/− mice (54% and 42%, respectively, P<0.05). Accumulation of aggregated platelets and their content of stromal cell-derived factor-1α (SDF-1α) at injury sites were significantly reduced in BM-Agtr1−/− (57% and 46%, respectively, P<0.05), accompanied by the decrease in the serum level of SDF-1α (28%, P<0.05). Thrombin-induced aggregation of Agtr1−/− platelets was markedly suppressed (45%, P<0.05). Finally, administration of adenosine diphosphate (ADP) receptor blocker ticlopidine markedly reduced platelet aggregation and their content of SDF-1α, concomitant with the decrease in number of circulating VPCs as well as vascular VPCs incorporated into neointima, resulting in a disappearance of an inhibitory effect of BM-AT1 deficiency on neointima formation after vascular injury. Furthermore, one week of administration of AT1 receptor blockade (ARB) after injury inhibited neointima formation (59%, P<0.05) concomitant with the reduced platelets aggregation and their content of SDF-1α followed by a decrease in number of circulating VPCs.
[CONCLUSION] The AT1 receptor in BM cells promotes neointima formation by regulating the mobilization and homing of BM-derived VPCs at sites of injury mainly through aggregated platelet-derived SDF-1α without any effects on EPC-mediated reendothelialization.