Vascular dysfunction in adult mice generated by assisted reproductive technologies

Abstract

Environmental influences acting early in life may predispose to premature cardiovascular disease. Assisted reproductive technologies (ART) involve the manipulation of early embryos at a time when they may be particularly vulnerable to external disturbances. We hypothesized ART predisposes to vascular dysfunction later in life.We therefore assessed vascular function in vitro (mesenteric artery) and in vivo (blood pressure, carotid artery) in young adult (10 wks) ART and control mice.In ART mice endothelium‐dependent mesenteric‐artery vasodilation in vitro was markedly impaired (P<.001 vs. control). This endothelial dysfunction in vitro was associated with arterial hypertension in vivo (108±4 vs. 103±4 mmHg, X±SE, P=.02, ART vs. ctrl). Most interestingly, male ART offspring transmitted their vascular dysfunction to the next generation, suggesting an epigenetic mechanism. To test for this possibility, we examined the effects of the histone deacetylase inhibitor Butyrate (2 mg/kg/day, i.p. for 2 wks) to male offspring of ART. Butyrate normalized vascular function in these animals (P<.001 vs. ctrls) and prevented the transmission of this defect to the next generation (P<0.001 butyrate vs. vehicle). We demonstrate for the first time that ART induces premature systemic vascular dysfunction in mice by an epigenetic mechanism. We speculate that ART may induce a similar problem in humans.Grant Funding Source: Swiss National Science Foundation