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

Abstract

Nitric oxide (NO) induces vasodilatatory, antiaggregatory, and antiproliferative effects in vitro. To delineate potential beneficial effects of NO in preventing vascular disease in vivo, we generated transgenic mice overexpressing human erythropoietin. These animals induce polyglobulia known to be associated with a high incidence of vascular disease. Despite hematocrit levels of 80%, adult transgenic mice did not develop hypertension or thromboembolism. Endothelial NO synthase levels, NO-mediated endothelium-dependent relaxation and circulating and vascular tissue NO levels were markedly increased. Administration of the NO synthase inhibitor N G -nitro-L-arginine methyl ester (L-NAME) led to vasoconstriction of peripheral resistance vessels, hypertension, and death of transgenic mice, whereas wild-type siblings developed hypertension but did not show increased mortality. L-NAMEtreated polyglobulic mice revealed acute left ventricular dilatation and vascular engorgement associated with pulmonary congestion and hemorrhage. In conclusion, we here unequivocally demonstrate that endothelial NO maintains normotension, prevents cardiovascular dysfunction, and critically determines survival in vivo under conditions of increased hematocrit.

Non-erythroid activities of erythropoietin: Functional effects on murine dendritic cells

“…The transgenic mouse over-expressing EPO (tg6) has been previously described (Heinicke et al, 2006;Katz et al, 2007;Ruschitzka et al, 2000). Female tg6 mice and their wt littermates were used at the age of 3-5 months.…”

“…More recently we noted EPO effects also on the humoral immune response of antigen-injected mice in both EPO-treated mice and tg6 mice (Ruschitzka et al, 2000;Vogel et al, 2003) -transgenic mice over-expressing human EPO (HuEPO) (Katz et al, 2007). Whereas these findings strongly suggest that EPO is an immunomodulator, the cellular mediators and underlying mechanisms are not understood, especially since EPO-Rs were not detected on lymphocytes ((Prutchi-Sagiv et al, 2006) and unpublished data).…”

Activation of the hypoxia‐inducible factor pathway induced by prolyl hydroxylase domain 2 deficiency enhances the effect of running training in mice

“…2000) showed that endothelial NO maintains normotension and critically determines the in vivo survival under conditions of increased haematocrit values under EPO overexpression. We, therefore, speculated that the NO level would be increased in Phd2 cKO mice.…”

“…A previous report showed that erythrocytotic mice neither developed hypertension nor displayed a change in heart rate or cardiac output, despite having haematocrit values of 80–90% in mice overexpressing EPO (Ruschitzka et al . 2000). They suggested that enhanced eNOS activity must have been due to increased blood viscosity that potentiates shear forces.…”

Constitutive excessive erythrocytosis causes inflammation and increased vascular permeability in aged mouse brain

“…Thus recombinant human Epo (rhEpo) is a frequently used therapeutic to increase red blood cell number and improve oxygen delivery. Excessive erythrocytosis however results in abnormally high blood viscosity and is often associated with severe clinical complications such as hypertension and thromboembolism (Bertinieri et al, 1998;Ruschitzka et al, 2000). Notably the effects of elevated Epo levels, and thus resultant high hematocrit, on blood vessel function and structure per se has not been fully 4 investigated.…”