Abstract 17552: Accelerated Vascular Lesion Formation in Mice Lacking All Nitric Oxide Synthases: Contribution of Bone Marrow Cells
Background: The precise role of nitric oxide synthases (NOSs) in vascular remodeling still remains to be fully elucidated. We addressed this issue in mice lacking all NOS genes.
Methods and Results: Permanent ligation of a unilateral carotid artery was performed in wild-type (WT), singly nNOS−/−, iNOS−/−, and eNOS−/−, and triply n/i/eNOS−/− mice (n=6–9). At 2 weeks after the carotid artery ligation, neointimal formation (NF), constrictive vascular remodeling (VR), and inflammatory leukocyte infiltration (LI) were noted in the ligated arteries of all genotypes. While NF (intima/media ratio: 0.19±0.02 in WT) was noted in eNOS−/− (0.58±0.03) and nNOS−/− genotypes (0.51±0.03), it was most accelerated in n/i/eNOS−/− genotype (1.01±0.08, P<0.01 vs. other strains). While VR (vascular circumference ratio, 0.95±0.05 in WT) was noted in iNOS−/− (0.79±0.02) and nNOS−/− genotypes (0.80±0.02), it was also most worsened in n/i/eNOS−/− genotype (0.70±0.03, P<0.05 vs. other strains). Moreover, while LI (cell number, 52±9 in WT) was noted in nNOS−/− (100±6), iNOS−/− (84±5) and eNOS−/− genotypes (94±6), it was again most aggravated in n/i/eNOS−/− genotype (272±23, P<0.01 vs. other strains). Although blood pressure (mmHg) (104±7.3 in WT) was significantly elevated in eNOS−/− (140±8.5) and n/i/eNOS−/− genotypes (143±3.1) (each P<0.05), those changes were not significantly correlated with the extents of the vascular lesion formation, indicating a minor role of hypertension. Finally, we studied the cell origin of vascular lesions. Bone marrow of WT, singly or triply NOS−/− genotype was transplanted into WT genotype, and 4 weeks later, the carotid artery ligation was performed. NI (0.31±0.15 vs. 0.67±0.20), VR (0.76±0.22 vs. 0.60±0.15), and LI (140±15 vs. 290±95) were all similarly most exacerbated in the case of n/i/eNOS−/− transplantation (all P<0.05), suggesting the contribution of bone marrow cells in the vascular lesion formation.
Conclusions: These results indicate that complete disruption of all NOS genes, especially in bone marrow cells, causes accelerated inflammatory vascular lesion formation caused by blood flow disruption in mice in vivo, demonstrating the critical role of the whole endogenous NOS system in preventing vascular remodeling.
- © 2010 by American Heart Association, Inc.