Maternal low-protein diet during mouse pre-implantation development induces vascular dysfunction and altered renin-angiotensin-system homeostasis in the offspring

School of Biological Sciences, University of Southampton, Bassett Crescent East, Southampton, UK.
The British journal of nutrition (Impact Factor: 3.45). 06/2010; 103(12):1762-70. DOI: 10.1017/S0007114509993783
Source: PubMed


Environmental perturbations during early mammalian development can affect aspects of offspring growth and cardiovascular health. We have demonstrated previously that maternal gestational dietary protein restriction in mice significantly elevated adult offspring systolic blood pressure. Therefore, the present study investigates the key mechanisms of blood pressure regulation in these mice. Following mating, female MF-1 mice were assigned to either a normal-protein diet (NPD; 18 % casein) or an isocaloric low-protein diet throughout gestation (LPD; 9 % casein), or fed the LPD exclusively during the pre-implantation period (3.5 d) before returning to the NPD for the remainder of gestation (Emb-LPD). All offspring received standard chow. At 22 weeks, isolated mesenteric arteries from LPD and Emb-LPD males displayed significantly attenuated vasodilatation to isoprenaline (P = 0.04 and P = 0.025, respectively), when compared with NPD arteries. At 28 weeks, stereological analysis of glomerular number in female left kidneys revealed no significant difference between the groups. Real-time RT-PCR analysis of type 1a angiotensin II receptor, Na+/K+ ATPase transporter subunits and glucocorticoid receptor expression in male and female left kidneys revealed no significant differences between the groups. LPD females displayed elevated serum angiotensin-converting enzyme (ACE) activity (P = 0.044), whilst Emb-LPD males had elevated lung ACE activity (P = 0.001), when compared with NPD offspring. These data demonstrate that elevated offspring systolic blood pressure following maternal gestational protein undernutrition is associated with impaired arterial vasodilatation in male offspring, elevated serum and lung ACE activity in female and male offspring, respectively, but kidney glomerular number in females and kidney gene expression in male and female offspring appear unaffected.

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Available from: Emma S Lucas, Feb 13, 2014
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    • "A maternal low protein diet fed during the preimplantation period of rat development caused blastocyst abnormalities and altered birth weight, postnatal growth rate, and adult hypertension [7], [8]. Similarly, a low protein diet administered exclusively during the preimplantation period in mice resulted in increased weight after birth, cardiovascular pathologies, perturbations to renin-angiotensin homeostasis, and abnormal anxiety-related behavior in the offspring [9], [10]. Furthermore, a maternal high fat diet prior to conception is associated with mouse oocytes and zygotes that have altered mitochondrial function including increased membrane potential and biogenesis and increased reactive oxygen species [11]. "
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    • "The RAS plays an important role in fetal growth restriction and the development of hypertension in response to maternal low-protein diet. Decreased nephron endowment and glomerular hypertrophy are accompanied by suppression of the newborn intrarenal RAS, system essential for normal kidney development [99–102]. In addition, maternal low-protein diet increases the risk of salt-sensitive hypertension [57]. "
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    • "Epidemiological and animal studies show that cardiovascular dysfunction, kidney disease, and alterations in the renin–angiotensin system might be related to the undernutrition state in critical stages of development and childhood (Benabe et al. 1993; Whorwood et al. 2001; Sesso et al. 2004; Barker 2007; Harrison and Langley- Evans 2009). Most of the effects of protein deficits on cardiac function have been evaluated during pregnancy, focusing on offspring development or the consequences of dramatic changes in the nutrition profile (Langley-Evans et al. 1994; Lucas 1995; Cheema et al. 2005; Prentice et al. 2005; Elmes et al. 2008; Watkins et al. 2010). For example, Cheema et al. (2005) showed that a low-protein (LP) diet during pregnancy induces cardiovascular dysfunction throughout the life of the offspring , indicated by decreased cardiac output and the maximum rates of contraction and relaxation, in addition to increased left ventricular end-diastolic pressure and cardiomyocyte apoptosis (Cheema et al. 2005). "
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