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Inter-organ cross-talk contributes to the pathogenesis of various disorders, and drug development based on inter-organ cross-talk is attracting attention. The roles of nitric oxide (NO) derived from the NO synthases system (NOSs) in inter-organ cross-talk remain unclear. We have investigated this issue by using our mice deficient in all three NOSs (triple n/i/eNOSs mice). We reported that 2/3 nephrectomized triple n/i/eNOSs mice die suddenly because of early onset of myocardial infarction, suggesting the protective role of NO derived from NOSs in the cross-talk 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 cross-talk 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 underwent triple n/i/eNOSs bone marrow transplantation as compared with those underwent wild-type bone marrow transplantation, suggesting the protective role of NO derived from NOSs in the cross-talk 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. We demonstrated in studies with triple n/i/eNOSs mice that partial nephrectomy accelerates the occurrence of myocardial infarction induced by systemic NOSs deficiency, 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 inter-organ cross-talk, indicating that systemic and myelocytic NOSs could be important therapeutic targets for myocardial infarction, vascular disease, and pulmonary hypertension.