Prenatal Nicotine Exposure Raises Male Blood Pressure via FTO-Mediated NOX2/ROS Signaling

Background: Cigarette smoking and nicotine exposure during pregnancy increase the risk of hypertension in offspring, though the mechanisms remain unclear. This study tested the hypothesis that m6A RNA hypomethylation epigenetically regulates vascular NOX (NADPH oxidase) and reactive oxygen species production, contributing to the development of a hypertensive phenotype in nicotine-exposed offspring.

Methods: Pregnant rats were exposed to episodic chronic intermittent nicotine aerosol (CINA) or saline aerosol control from gestational day 4 to day 21. Experiments were conducted on the 6-month-old adult offspring.

Results: CINA exposure during pregnancy heightened the Ang II (angiotensin II)-stimulated blood pressure response in male offspring but not in females. Furthermore, CINA increased vascular NOX2 expression and superoxide production specifically in male offspring. Inhibition of NOX2 with gp91ds-tat, both ex vivo and in vivo, reduced CINA-induced increases in superoxide production and blood pressure response. Notably, CINA elevated vascular m6A demethylase FTO (fat mass and obesity-associated protein) expression, while decreasing total vascular m6A levels and the m6A methylation of the NOX2 gene. Additionally, inhibiting FTO with FB23-2 ex vivo reduced CINA-induced increases in vascular NOX2 expression. In vitro studies using human umbilical vein endothelial cells showed that nicotine upregulated FTO and NOX2 protein levels in a dose-dependent manner, which was reversed by FTO inhibition with FB23-2 or FTO knockdown via siRNAs.

Conclusions: This study reveals a novel mechanism where m6A demethylase FTO mediates epigenetic upregulation of vascular NOX2 signaling in the development of a hypertensive phenotype due to CINA exposure. These findings could provide a potential therapeutic target for preventing and treating developmental hypertension.