Fetal origins of adult vascular dysfunction in mice lacking endothelial nitric oxide synthase

Monica Longo, Venu Jain, Yuri P. Vedernikov, Radek Bukowski, Robert E. Garfield, Gary D. Hankins, Garland D. Anderson, George R. Saade
2005 American Journal of Physiology. Regulatory Integrative and Comparative Physiology  
Epidemiological studies have shown increased incidence of hypertension and coronary artery disease in growth-restricted fetuses during their adult life. A novel animal model was used to test the hypothesis regarding the role of an abnormal uterine environment in fetal programming of adult vascular dysfunction. Mice lacking a functional endothelial nitric oxide synthase (NOS3 Ϫ/ϪKO , where KO is knockout) and wild-type (WT) mice (NOS3 ϩ/ϩWT ) were crossbred to produce homozygous NOS3 Ϫ/ϪKO ,
more » ... us NOS3 Ϫ/ϪKO , maternally derived heterozygous (NOS3 ϩ/Ϫmat , mother with NOS3 deficiency), paternally derived heterozygous (NOS3 ϩ/Ϫpat , normal mother), and NOS3 ϩ/ϩWT litters. Number of fetuses per litter was smaller in NOS3 Ϫ/ϪKO and NOS3 ϩ/Ϫmat compared with NOS3 ϩ/Ϫpat and NOS3 ϩ/ϩWT mice. Adult female mice from these litters (7-8 wk old) were killed, and ring preparations of carotid and mesenteric arteries were mounted in a wire myograph to evaluate the passive and reactive vascular characteristics. Slope of the length-tension plot (a measure of vascular compliance) was increased, and optimal diameter (as calculated by Laplace equation) was decreased in NOS3 Ϫ/ϪKO and NOS3 ϩ/Ϫmat compared with NOS3 ϩ/Ϫpat and NOS3 ϩ/ϩWT mice. Acetylcholine caused vasorelaxation in NOS3 ϩ/Ϫpat and NOS3 ϩ/ϩWT and contraction in NOS3 Ϫ/ϪKO and NOS3 ϩ/Ϫmat mice. Responses to phenylephrine and Ca 2ϩ were increased in NOS3 Ϫ/ϪKO and NOS3 ϩ/Ϫmat compared with NOS3 ϩ/Ϫpat and NOS3 ϩ/ϩWT mice. Relaxation to isoproterenol was decreased in NOS3 Ϫ/ϪKO and NOS3 ϩ/Ϫmat vs. NOS3 ϩ/Ϫpat and NOS3 ϩ/ϩWT mice. Abnormalities in the passive and reactive in vitro vascular properties seen in NOS ϩ/Ϫmat that developed in a NOS3-deficient maternal/uterine environment compared with the genetically identical NOS3 ϩ/Ϫpat mice that developed in a normal environment are the first direct evidence in support of a role for uterine environment in determining vascular function in later life. fetal origin of adult disease; pregnant mice; uterine environment; vascular reactivity in vitro IN 1986, BARKER AND OSMOND (6) proposed that the intrauterine environment impacts a fetus well beyond the perinatal period. Stimuli or insults to the fetus during the critical period of development lead to fetal programming and produce adaptive changes in the fetal anatomy, physiology, and metabolism that Address for reprint requests and other correspondence: M. Longo,
doi:10.1152/ajpregu.00367.2004 pmid:15626780 fatcat:yktlaxobxnh2jl22r2kwauvm7e