Maternal Protein Restriction During Mouse Preimplantation Development Induces Vascular Dysfunction and Altered Renin-angiotensin-system Homeostasis in the Offspring.

Abstract

Studies using rodent and domestic animal models have demonstrated that environmental conditions experienced during early development, either in vivo or in vitro, shape critical aspects of future growth, metabolism, physiology and cardiovascular health. In particular, we have previously demonstrated that maternal dietary protein restriction during discrete windows of gestation results in the development of hypertension in the adult mouse. Therefore, the aim of the current study was to investigate the potential mechanisms involved in the development of hypertension following maternal protein underntrtion. Following mating, virgin female MF-1 mice were randomly assigned to either normal protein diet for the entirety of gestation (NPD; 18% casein), isocaloric low protein diet for the entirety of gestation (LPD; 9% casein), or LPD exclusively during the preimplantation period (3.5 days), before returning to NPD for the remainder of gestation (Emb-LPD). At birth all litters were standardised to a mean of 6 (3 male and 3 females where possible). At 22 weeks of age, isolated mesenteric arteries from LPD and Emb-LPD males displayed attenuated responsiveness to the endothelial-independent vasodilator isoprenaline (P <0.04) and a trend towards an impaired responsiveness to the nitric oxide donor sodium nitroprusside (P <0.01) when compared to NPD arteries. At 28 weeks of age, female left kidneys were processed in glycol methacrylate, sectioned and, using stereological techniques, glomerular number was estimated using the physical fractionator principle. No difference was observed in mean female left kidney glomerular number between any of the treatment groups. LPD females displayed a significantly elevated serum angiotensin converting enzyme (ACE) activity (P =0.05), while Emb-LPD males and females had a significantly elevated lung ACE activity when compared to NPD offspring (P <0.05). These data demonstrate that maternal dietary protein restriction during discrete windows of gestation (preimplantation development, 3.5 days) programmes postnatal cardiovascular abnormalities through the development of vasodilator dysfunction in male resistance arteries, elevated ACE activity, but with minimal effects on kidney morphology.