Elevated blood pressures in mice lacking endothelial nitric oxide synthase.
Nitric oxide produced in endothelial cells affects vascular tone. To investigate the role of endothelial nitric oxide synthase (eNOS) in blood pressure regulation, we have generated mice heterozygous (+/-) or homozygous (-/-) for disruption of the eNOS gene. Immunohistochemical staining with anti-eNOS antibodies showed reduced amounts of eNOS protein in +/- mice and absence of eNOS protein in -/- mutant mice. Male or female mice of all three eNOS genotypes were indistinguishable in general appearance and histology, except that -/- mice had lower body weights than +/+ or +/- mice. Blood pressures tended to be increased (by approximately 4 mmHg) in +/- mice compared with +/+, while -/- mice had a significant increase in pressure compared with +/+ mice (approximately 18 mmHg) or +/- mice (approximately 14 mmHg). Plasma renin concentration in the -/- mice was nearly twice that of +/+ mice, although kidney renin mRNA was modestly decreased in the -/- mice. Heart rates in the -/- mice were significantly lower than in +/- or +/+ mice. Appropriate genetic controls show that these phenotypes in F2 mice are due to the eNOS mutation and are not due to sequences that might differ between the two parental strains (129 and C57BL/6J) and are linked either to the eNOS locus or to an unlinked chromosomal region containing the renin locus. Thus eNOS is essential for maintenance of normal blood pressures and heart rates. Comparisons between the current eNOS mutant mice and previously generated inducible nitric oxide synthase mutants showed that homozygous mutants for the latter differ in having unaltered blood pressures and heart rates; both are susceptible to lipopolysaccharide-induced death.
Shesely
E G
EG
Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill 27599, USA.
Maeda
N
N
Kim
H S
HS
Desai
K M
KM
Krege
J H
JH
Laubach
V E
VE
Sherman
P A
PA
Sessa
W C
WC
Smithies
O
O
D000704:Analysis of Variance; D000818:Animals; D001794:Blood Pressure; D002417:Cattle; D002678:Chimera; D017931:DNA Primers; D004730:Endothelium, Vascular / Q000201:enzymology*; D005260:Female; D005838:Genotype; D006579:Heterozygote; D006973:Hypertension / Q000235:genetics* / Q000503:physiopathology*; D007527:Isoenzymes / Q000172:deficiency / Q000235:genetics; D007668:Kidney / Q000201:enzymology; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000172:deficiency* / Q000235:genetics; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D012083:Renin / Q000096:biosynthesis / Q000097:blood; D013234:Stem Cells; D014158:Transcription, Genetic
D017931:DNA Primers; D007527:Isoenzymes; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D019001:Nitric Oxide Synthase; D012083:Renin