Metformin Exposure in uteroProgrammes Hypertension in a Sex‐Specific Manner in Adult Offspring of Obese Mice

Abstract

IntroductionMetformin is the first‐line pharmacological treatment for gestational diabetes in many countries. Although effective at improving maternal glycaemia, metformin readily crosses the placenta and could directly affect the fetus. Indeed, metformin exposure in utero increases postnatal adiposity. However, other long‐term effects on offspring exposed to metformin in utero have not been investigated. Here we explored the impact of maternal metformin treatment during obese, glucose‐intolerant pregnancy on offspring cardiovascular function at one year of age using an established mouse model of maternal diet‐induced obesity.MethodsFemale C57Bl/6J mice were fed either a standard chow diet [Control dams (Con)] or an obesogenic diet [Obese (Ob) and Obese‐Metformin (Ob‐Met) dams] from weaning up to and including pregnancy and lactation. Ob‐Met dams received a clinically relevant dose of metformin orally from one week prior to mating until day 19 of gestation. All offspring were weaned onto standard chow fed ad libitum at three weeks of age. At one year of age, systolic blood pressure (SBP) was measured by tail cuff plethysmography in the conscious animal and echocardiography was performed under anaesthesia. Post‐mortem, femoral arteries were isolated and vasomotor reactivity tested using in vitro wire myography. Myography dose‐response curves were analysed using mixed effects models, all other data were analysed by One‐Way ANOVA. Post‐hoc multiple comparisons were performed where appropriate. Significance was accepted when P<0.05.ResultsRelative to controls, female offspring of Ob‐Met dams had increased SBP. However, no differences in SBP were observed in male offspring (Fig.1A). Female offspring of both Ob and Ob‐Met dams had enhanced femoral vasoconstrictor reactivity to K+ (Fig. 1B) but normal cardiac function (Fig. 1C). In contrast, male offspring of both Ob and Ob‐Met dams showed indices of diastolic dysfunction (Fig. 1C) and male offspring of Ob‐Met dams had enhanced femoral vasoconstrictor reactivity to phenylephrine (PE) (Fig.1B).ConclusionsMaternal obesity and metformin exposure in utero caused sex‐specific changes in cardiovascular function in 12‐month‐old offspring. In female offspring, exposure to maternal obesity and metformin programmed hypertension with enhanced peripheral vasoconstrictor reactivity. In male offspring, maternal obesity alone programmed echocardiographic indices of left ventricular restrictive filling which were not corrected by metformin treatment, while combined exposure to maternal obesity and metformin also programmed enhanced peripheral vasoconstrictor reactivity. These findings provide novel insight into the long‐term effects of in utero metformin exposure on the cardiovascular health of the next generation in obese pregnancy, and highlight the importance of considering offspring sex in developmental programming studies.