Protective role of the nitric oxide synthases system in inter-organ communication

Abstract

The role of the nitric oxide synthases (NOSs) system in inter-organ communication is not fully understood. We addressed this point in our mice lacking all three NOS isoforms (triple n/i/eNOSs-/- mice). We previously reported that the triple n/i/eNOSs-/- mice spontaneously develop myocardial infarction. However, it takes a long time (approximately 1 year) to develop myocardial infarction. We then revealed that 2/3-nephrectomized triple n/i/eNOSs-/- mice suddenly die due to early onset of myocardial infarction, succeeding in developing an experimentally useful model of myocardial infarction. These results suggest the protective role of NOSs in reno-cardiac communication. We next studied the role of NOSs in bone marrow cells (BM) in vascular lesion formation. Constrictive vascular remodeling and neointimal formation at 14 days after carotid artery ligation were markedly accelerated in wild-type (WT) mice transplanted with triple n/i/eNOSs-/- BM as compared with those with WT BM. These results suggest the protective role of NOSs in BM-vascular communication. We then investigated the role of NOSs in BM in pulmonary hypertension (PH). The extents of PH at 3 weeks after hypoxic exposure were markedly exacerbated in WT mice transplanted with triple n/i/eNOSs-/- BM as compared with those with WT BM, suggesting the protective role of NOSs in BM-lung communication. These lines of evidence indicate that systemic and BM NOSs may be a novel therapeutic target in MI, vascular disease, and PH.