Nitric oxide prevents cardiovascular disease and determines survival in polyglobulic mice overexpressing erythropoietin

Nitric oxide (NO) induces vasodilatatory, antiaggregatory, and antiprolifer ative effects in vitro. To delineate potential beneficial effects of NO in preventing vascular disease in vivo, we generated transgenic mice overexpre ssing human erythropoietin. These animals induce polyglobulia known to be a ssociated with a high incidence of vascular disease. Despite hematocrit lev els of 80%, adult transgenic mice did not develop hypertension or thromboem bolism. Endothelial NO synthase levels, NO-mediated endothelium-dependent r elaxation and circulating and vascular tissue NO levels were markedly incre ased. Administration of the NO synthase inhibitor N-G-nitro-L-arginine meth yl ester (L-NAME) led to vasoconstriction of peripheral resistance vessels, hypertension, and death of transgenic mice, whereas wild-type siblings dev eloped hypertension bur did not show increased mortality. L-NAME-treated po lyglobulic mice revealed acute left ventricular dilatation and vascular eng orgement associated with pulmonary congestion and hemorrhage. In conclusion , we here unequivocally demonstrate that endothelial NO maintains normotens ion, prevents cardiovascular dysfunction, and critically determines surviva l in vivo under conditions of increased hematocrit.