Effect of subsequent pregnancy on vascular function in endothelial nitric oxide synthase (NOS3) knockout mice

Abstract

Nitric oxide is involved in gestational vascular adaptation and its deficiency has been implicated in preeclampsia, and the endothelial nitric oxide synthase (NOS3) inhibition results in a preeclampsia-like condition in various animal models.Our objective was to test the hypothesis that the lower risk of preeclampsia after the first pregnancy is related to improved vascular adaptation. Female NOS3 knockout (C57BL/6J-NOS3−/−KO) and wild-type (NOS3+/+WT) were sacrificed at day 18 of gestation in their first (P0) or second (P1) pregnancy. The carotid arteries were placed in a wire myograph for isometric tension recording. Maximal relaxation to acetylcholine (Ach), maximal contraction to KCl, and vascular responses to cumulative concentrations of phenylephrine (PE) and serotonin (5-HT) were determined. One-way ANOVA followed by Neuman-Keuls post hoc test were used for statistical analysis (significance: p<0.05). The maximal contraction to KCl and vascular response to PE were significantly higher in knockout P0 females when compared to all other groups. Interestingly the responses to KCl in the knockout P1 females were not significantly different from wild-type P0 and P1 females. Similarly, the vascular sensitivity to 5-HT was significantly increased in knockout P0, while was similar between knockout P1 females and the wild type P0 and P1 pregnant female. Relaxation to Ach was absent in knockout P0 females, but was partially regained in knockout P1 females. These findings support that mice lacking NOS3 function have altered vascular adapatation to pregnancy in their first but not second pregnancy. The normalizaton of vascular function with subsequent pregnancy may underly the mechanism responsible for decreased risk of preeclampsia after the first pregnancy. Elucidation of these mechanisms may be important for understanding the etiology of preeclampsia.