Abstract 729: Bone Marrow Angiotensin AT1 and AT2 Receptors Differentially Modulate Vascular Repair by Regulating Mobilization and Activation of Bone Marrow-Derived Vascular Progenitors
[BACKGROUND] Bone marrow (BM) cells and angiotensin II (Ang II) are involved in vascular repair after arterial injury, whereas Ang II-mediated action on BM cells remains undefined.
[METHOD AND RESULT] Total BM cells from AT1-deficient (Agtr1−/−), AT2-deficient (Agtr2−/−), or WT mice were transplanted into BM-ablated WT mice. A spring-wire was inserted into the femoral artery and analyzed 4 weeks after injury. WT mice reconstituted with Agtr1−/− marrow (WT/BM-Agtr1−/−) showed a significant reduction in neointimal formation compared with control mice (47%, P<0.05), whereas it was markedly exaggerated in WT mice reconstituted with Agtr2−/− marrow (WT/BM-Agtr2−/−) (103%, P<0.05). The number of MOMA-2-positive cells in intimal lesion was markedly reduced by 72% (P<0.05) in BM-Agtr1−/− mice, whereas the number of MOMA-2-positive cells in adventitia was increased by 33% (P<0.05) in BM-Agtr2−/−mice compared with BM-WT mice. The number of CCR2+ monocytes moderately increased in BM-Agtr2−/− mice (61%, P<0.05). We next examined the effect of BM-AT1 and BM-AT2 receptor on the mobilization and recruitment of potential vascular progenitor cells (VPCs), determined as c-kit−Sca-1+Lin− cell markers. The number of circulating potential VPCs was significantly decreased in BM-Agtr1−/− mice compared with BM-WT mice (56 ± 12 and 122 ± 19 cells/μl, respectively, P<0.05), whereas no difference could be observed between the BM-Atgr2−/− and BM-WT mice. In contrast, the frequencies of CXCR4+ VPCs were significantly increased in BM-Agtr2−/− mice compared with the other two groups (110%, P<0.05). Moreover, the accumulation of Sca-1+ cells in intimal lesion was attenuated in BM-Agtr1−/− mice (68%, P<0.05), whereas BM-Agtr2−/− mice showed an increased accumulation of Sca-1+ cells in adventitia (48%, P<0.05).
[CONCLUSION] AT2-mediated signals on BM-MNCs inhibited neointimal formation after arterial injury; in contrast AT1 deteriorated the lesions. BM-AT1 and BM-AT2 differentially regulates the mobilization and activation of BM-derived vascular progenitors, suggesting that BM-AT2 could be an alternative target for the prevention of cardiovascular event.