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Effect of Smoking and Smoking Cessation during Pregnancy on Endothelial Function

Malene Rohr Andersen



Pregnant smokers have retarded fetal growth compared to non-smokers and those who stop smoking early in pregnancy (ex-smokers). The reason for this is unknown but one possibility is that reduced production of the vasodilator nitric oxide (NO) in the fetal vessels and in uterine arteries of pregnant smokers may lower the delivery of nutrient to the fetus and result in retarded fetal growth. The overall purpose of this thesis therefore was to investigate the effect of smoking and smoking cessation during pregnancy on endothelial function in vessels of importance for maintaining fetal growth in uterus. The present thesis aimed to address this purpose in two studies:

Study I; by determination of endothelial nitric oxide synthase (eNOS) activity and concentration in fetal umbilical and chorionic vessels from non-smokers, smokers, and ex-smokers, and by relating these findings to the size of the newborn, and Study II; by determination of the endothelial-dependent bradykinin-mediated vasodilator function in uterine small arteries from pregnant non-smokers, smokers, and ex-smokers. 

Methods: Study I: Is an observational study of 266 healthy, singleton pregnancies. Self-reported smoking was verified by serum cotinine; 182 were non-smokers, 43 were smokers, and 41 stopped smoking in pregnancy. The eNOS activity and concentration were quantified in endothelial cells of fetal umbilical and chorionic vessels. Furthermore, serum estradiol and plasma L-arginine and dimethylarginines, that may affect NO production, were determined in maternal blood samples and in fetal blood samples obtained from the umbilical cord immediately after delivery. Study II: Is a small observational study of 29 healthy, singleton pregnancies scheduled for Cesarean section. Self-reported smoking was verified by serum cotinine; 12 were non-smokers, 9 were smokers, and 8 stopped smoking in pregnancy. Uterine arteries were dissected from myometrial biopsies and vascular function assessed on a small vessel wire myograph. 

Results and Conclusions: Study I: Newborns of smokers had a lower weight (P_0.001), a smaller head circumference (P_0.041), and were shorter (P_0.001) than were newborns of nonsmokers and ex-smokers. The eNOS activity in umbilical veins of smokers was 36% lower (P<0.001) and the eNOS concentration 47% lower (P<0.001) than that of nonsmokers, while the same levels were found in umbilical veins from ex-smokers and nonsmokers. The same pattern in eNOS activity and concentration was found in umbilical arteries and chorionic vessels. Non-smokers, smokers, and ex-smokers had similar levels of serum estradiol and plasma L-arginine and dimethylarginines. The findings suggest that maternal smoking reduces eNOS activity in the fetal vascular bed contributing to retarded fetal growth caused by reducing the vasodilatory capacity. Equally important, smoking cessation early in pregnancy prevents these effects in the newborns. Study II: Newborns of smokers were shorter (P<0.05) and had a smaller head circumference (P<0.05) compared to those of non-smokers, but newborns of exsmokers were similar to those of smokers and non-smokers. Preconstricted arteries from non-smokers had a better bradykinin-induced relaxation than arteries from smokers and ex-smokers (P<0.05). In the presence of NG-nitro-L-arginine (eNOS inhibitor), arteries from smokers and ex-smokers did not relax to bradykinin, while arteries from non-smokers still relaxed at high concentrations of bradykinin (P<0.05). When NG-nitro-L-arginine and indomethacin (cyclooxygenase inhibitor) were present simultaneously arteries from non-smokers no longer responded to bradykinin. Relaxations to sodium nitroprusside (NO donor) were similar in arteries from nonsmokers and smokers, but were increased in arteries from ex-smokers when compared with those from non-smokers (P<0.05). The findings suggest that maternal smoking reduces NO and vasodilator prostanoid-mediated relaxation in uterine small arteries contributing to retarded fetal growth. Apparently, smoking cessation early in pregnancy does not prevent this effect on uterine arteries, but may increase smooth muscle sensitivity to NO.