Significance of nitric oxide derived from the nitric oxide synthases system in cardiovascular interorgan crosstalk.

Interorgan crosstalk contributes to the pathogenesis of various disorders, and drug development based on interorgan crosstalk is attracting attention. The roles of nitric oxide (NO) derived from the NO synthases system (NOSs) in interorgan crosstalk remain unclear. We have investigated this issue by using our mice deficient in all 3 NOSs (triple n/i/eNOSs-/- mice). We reported that 2/3 nephrectomized triple n/i/eNOSs-/- mice die suddenly because of the early onset of myocardial infarction, suggesting the protective role of NO derived from NOSs in the crosstalk between the kidney and the heart. We studied the role of NO derived from NOSs expressed in the bone marrow in vascular lesion formation. Constrictive arterial remodeling and neointimal formation following unilateral carotid artery ligation were prominently aggravated in wild-type mice transplanted with triple n/i/eNOSs-/- bone marrow cells as compared with those with wild-type bone marrow cells, suggesting the protective role of NO derived from NOSs in the crosstalk between the bone marrow and the blood vessel. We further investigated the role of NO derived from NOSs expressed in the bone marrow in pulmonary hypertension. The extent of pulmonary hypertension after chronic hypoxic exposure was markedly exacerbated in wild-type mice that underwent triple n/i/eNOSs-/- bone marrow transplantation as compared with those that underwent wild-type bone marrow transplantation, suggesting the protective role of NO derived from NOSs in the crosstalk between the bone marrow and the lung. These lines of evidence demonstrate that systemic and myelocytic NOSs could be novel therapeutic targets for myocardial infarction, vascular disease, and pulmonary hypertension. SIGNIFICANCE STATEMENT: This study demonstrated partial nephrectomy accelerates the occurrence of myocardial infarction induced by systemic NOSs deficiency in triple n/i/eNOSs-/- mice, that myelocytic NOSs deficiency aggravates vascular lesion formation after unilateral carotid artery ligation, and that myelocytic NOSs deficiency exacerbates chronic hypoxia-induced pulmonary hypertension. These results suggest that NO derived from NOSs plays a protective role in cardiovascular interorgan crosstalk, indicating that systemic and myelocytic NOSs could be important therapeutic targets for myocardial infarction, vascular disease, and pulmonary hypertension.