British Journal of Nutrition

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British Journal of Nutrition (2010), 103:1762-1770 Cambridge University Press
Copyright © The Authors 2010

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Developmental Biology

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

Adam J. Watkinsa1 c1, Emma S. Lucasa1, Christopher Torrensa2, Jane K. Cleala2, Lauren Greena1, Clive Osmonda3, Judith J. Eckerta1a2, William P. Graya4, Mark A. Hansona2 and Tom P. Fleminga1

a1 School of Biological Sciences, University of Southampton, Bassett Crescent East, Southampton SO16 7PX, UK
a2 Institute of Developmental Sciences, Developmental Origins of Health and Disease (DOHaD) Division, School of Medicine, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK
a3 MRC Epidemiology Resource Centre, Southampton General Hospital, Southampton SO16 6YD, UK
a4 Division of Clinical Neurosciences, School of Medicine, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK
Article author query
watkins aj [PubMed]  [Google Scholar]
lucas es [PubMed]  [Google Scholar]
torrens c [PubMed]  [Google Scholar]
cleal jk [PubMed]  [Google Scholar]
green l [PubMed]  [Google Scholar]
osmond c [PubMed]  [Google Scholar]
eckert jj [PubMed]  [Google Scholar]
gray wp [PubMed]  [Google Scholar]
hanson ma [PubMed]  [Google Scholar]
fleming tp [PubMed]  [Google Scholar]


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.

(Received July 15 2009)

(Revised December 08 2009)

(Accepted December 10 2009)

(Online publication February 04 2010)

Key Words:CVD; Maternal diet; Pre-implantation embryo development


c1 Corresponding author: Dr Adam Watkins, fax +44 2380 594459, email


Abbreviations: ACE, angiotensin-converting enzyme; Emb-LPD, low-protein diet for the first 3·5 d before switching to normal diet for the remainder of gestation; LPD, low-protein diet; NPD, normal-protein diet; pEC50,  − log effective concentration equal to 50 % of the maximal response; RAS, renin–angiotensin system; SBP, systolic blood pressure