Abstract
ObjectiveMaternal cigarette smoking/nicotine use during pregnancy is associated with an increased risk of cardiovascular diseases and development of hypertensive phenotype in later life. However, the involved molecular pathway is remain unclear. The present study tested the hypothesis that cigarette smoking‐relevant nicotine inhalation during pregnancy causes a gender‐dependent change the balance of resistance vasculatures eNOS and prooxidant functions in adult offspring, leading to development of hypertensive phenotype in adult male offspring.MethodsThe time‐dated pregnant rats were exposed to chronic intermittent nicotine aerosol (CINA) via a novel lung alveolar region‐targeted aerosol method during pregnancy (E4 to E20). Experiments were performed in adult (~6 month‐old) offspring.ResultsCINA exposure enhanced vascular H2O2 production which was inhibited by eNOS inhibitor, L‐NAME in male offspring. CINA exposure selectively enhanced vascular NOX2 expression. CINA exposure enhanced angiotensin II (Ang II)‐induced BP response in male offspring, which was not affected by NOX2 inhibitor (gp91 ds‐tat) but significantly reversed by L‐NAME or BH4 treatment in vivo. In pressure myography experiments. CINA exposure had no effect on pressure‐induced myogenic tone but decreased the Acetylcholine (Ach)‐induced relaxation in adult male but not female offspring. In the presence of L‐NAME or H2O2 scavenger (PEG‐catalase), there were no differences of Ach‐induced relaxation between CINA and saline control offspring. Furthermore, pretreatment of eNOS cofactor BH4 enhanced Ach‐induced relaxation in CINA‐exposed male offspring, while no effect in saline control group. In addition, exogenous NO donor (SNP)‐induced mesenteric artery relaxations were similar between CINA exposed and saline control male offspring.ConclusionsThese findings provide novel evidence that maternal inhaled nicotine exposure could impair fetal vascular development and induce a gender‐dependent development of endothelial dysfunction phenotype in adult male offspring via enhancing vascular eNOS uncoupling. The uncoupled eNOS‐mediated ROS plays a predominant role in CINA‐induced hypertensive response in male offspringSupport or Funding InformationSupported in part by the NIH grants: R01HL135623, R03DA041492, and R01HD088039; TRDRP grants: 29IR0437 and T30FT0936
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