Skip to main content
    • Aa
    • Aa
  • Access
  • Cited by 37
  • Cited by
    This article has been cited by the following publications. This list is generated based on data provided by CrossRef.

    Green, Lucy R. and Hanson, Mark A. 2017. Fetal and Neonatal Physiology.

    Chisaka, Toshiyuki Mogi, Masaki Nakaoka, Hirotomo Kan-no, Harumi Tsukuda, Kana Wang, Xiao-Li Bai, Hui-Yu Shan, Bao-Shuai Kukida, Masayoshi Iwanami, Jun Higaki, Takashi Ishii, Ei-ichi and Horiuchi, Masatsugu 2016. Low-Protein Diet-Induced Fetal Growth Restriction Leads to Exaggerated Proliferative Response to Vascular Injury in Postnatal Life. American Journal of Hypertension, Vol. 29, Issue. 1, p. 54.

    Hansen, Peter J. Dobbs, Kyle B. Denicol, Anna C. and Siqueira, Luiz G. B. 2016. Sex and the preimplantation embryo: implications of sexual dimorphism in the preimplantation period for maternal programming of embryonic development. Cell and Tissue Research, Vol. 363, Issue. 1, p. 237.

    Loche, Elena and Ozanne, Susan E. 2016. Early nutrition, epigenetics, and cardiovascular disease. Current Opinion in Lipidology, Vol. 27, Issue. 5, p. 449.

    Lunde, Emilie R. Washburn, Shannon E. Golding, Michael C. Bake, Shameena Miranda, Rajesh C. and Ramadoss, Jayanth 2016. Alcohol-Induced Developmental Origins of Adult-Onset Diseases. Alcoholism: Clinical and Experimental Research, Vol. 40, Issue. 7, p. 1403.

    Moritz, Karen M. 2016. Kidney Development, Disease, Repair and Regeneration.

    Sengupta, Priyodarshi and Bhattacharya, Niranjan 2016. Human Fetal Growth and Development.

    Sun, Congshan Velazquez, Miguel A. and Fleming, Tom P. 2016. The Epigenome and Developmental Origins of Health and Disease.

    Velazquez, Miguel A. Sun, Congshan and Fleming, Tom P. 2016. The Epigenome and Developmental Origins of Health and Disease.

    Fleming, Tom P. Watkins, Adam J. Sun, Congshan Velazquez, Miguel A. Smyth, Neil R. and Eckert, Judith J. 2015. Do little embryos make big decisions? How maternal dietary protein restriction can permanently change an embryo’s potential, affecting adult health. Reproduction, Fertility and Development, Vol. 27, Issue. 4, p. 684.

    Fleming, T. P. Velazquez, M. A. and Eckert, J. J. 2015. Embryos, DOHaD and David Barker. Journal of Developmental Origins of Health and Disease, Vol. 6, Issue. 05, p. 377.

    Gebhardt, Kathryn and Zander-Fox, Deirdre 2015. Handbook of Fertility.

    Lane, Michelle Zander-Fox, Deirdre L. Robker, Rebecca L. and McPherson, Nicole O. 2015. Peri-conception parental obesity, reproductive health, and transgenerational impacts. Trends in Endocrinology & Metabolism, Vol. 26, Issue. 2, p. 84.

    Latham, Keith E. 2015.

    Morgado, Joana Sanches, Bruno Anjos, Rui and Coelho, Constança 2015. Programming of Essential Hypertension: What Pediatric Cardiologists Need to Know. Pediatric Cardiology, Vol. 36, Issue. 7, p. 1327.

    Sun, Zhaoxia Hu, Shuangshuang Zuo, Na Yang, Shuailong He, Zheng Ao, Ying and Wang, Hui 2015. Prenatal nicotine exposure induced GDNF/c-Ret pathway repression-related fetal renal dysplasia and adult glomerulosclerosis in male offspring. Toxicol. Res., Vol. 4, Issue. 4, p. 1045.

    Watkins, A. J. Lucas, E. S. Marfy-Smith, S. Bates, N. Kimber, S. J. and Fleming, T. P. 2015. Maternal nutrition modifies trophoblast giant cell phenotype and fetal growth in mice. Reproduction, Vol. 149, Issue. 6, p. 563.

    Yzydorczyk, C. Mitanchez, D. Boubred, F. and Simeoni, U. 2015. Glucose Intake and Utilization in Pre-Diabetes and Diabetes.

    Chavatte-Palmer, Pascale Lee, Rita Bertolini, Marcelo Jammes, Hélène Schmidt, Mette and Callesen, Henrik 2014. Principles of Cloning.

    Clough, Geraldine F. 2014. Comprehensive Physiology.


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

  • Adam J. Watkins (a1), Emma S. Lucas (a1), Christopher Torrens (a2), Jane K. Cleal (a2), Lauren Green (a1), Clive Osmond (a3), Judith J. Eckert (a1) (a2), William P. Gray (a4), Mark A. Hanson (a2) and Tom P. Fleming (a1)
  • DOI:
  • Published online: 04 February 2010

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.

  • View HTML
    • Send article to Kindle

      To send this article to your Kindle, first ensure is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle.

      Note you can select to send to either the or variations. ‘’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

      Find out more about the Kindle Personal Document Service.

      Maternal low-protein diet during mouse pre-implantation development induces vascular dysfunction and altered renin–angiotensin-system homeostasis in the offspring
      Available formats
      Send article to Dropbox

      To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your Dropbox account. Find out more about sending content to Dropbox.

      Maternal low-protein diet during mouse pre-implantation development induces vascular dysfunction and altered renin–angiotensin-system homeostasis in the offspring
      Available formats
      Send article to Google Drive

      To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your Google Drive account. Find out more about sending content to Google Drive.

      Maternal low-protein diet during mouse pre-implantation development induces vascular dysfunction and altered renin–angiotensin-system homeostasis in the offspring
      Available formats
Corresponding author
*Corresponding author: Dr Adam Watkins, fax +44 2380 594459, email
Linked references
Hide All

This list contains references from the content that can be linked to their source. For a full set of references and notes please see the PDF or HTML where available.

1DJ Barker (2002) Fetal programming of coronary heart disease. Trends Endocrinol Metab 13, 364368.

2MA Hanson & PD Gluckman (2008) Developmental origins of health and disease: new insights. Basic Clin Pharmacol Toxicol 102, 9093.

3IC McMillen & JS Robinson (2005) Developmental origins of the metabolic syndrome: prediction, plasticity, and programming. Physiol Rev 85, 571633.

4L Brawley , S Itoh , C Torrens , (2003) Dietary protein restriction in pregnancy induces hypertension and vascular defects in rat male offspring. Pediatr Res 54, 8390.

5LJ Edwards & IC McMillen (2002) Periconceptional nutrition programs development of the cardiovascular system in the fetal sheep. Am J Physiol Regul Integr Comp Physiol 283, R669R679.

6SC Langley & AA Jackson (1994) Increased systolic blood pressure in adult rats induced by fetal exposure to maternal low protein diets. Clin Sci (Lond) 86, 217222.

7C Torrens , L Brawley , A Barker , (2003) Maternal protein restriction in the rat impairs resistance artery but not conduit artery function in pregnant offspring. J Physiol 547, 7784.

8C Torrens , L Brawley , F Anthony , (2006) Folate supplementation during pregnancy improves offspring cardiovascular dysfunction induced by protein restriction. Hypertension 47, 982987.

9JK Cleal , KR Poore , JP Boullin , (2007) Mismatched pre- and postnatal nutrition leads to cardiovascular dysfunction and altered renal function in adulthood. Proc Natl Acad Sci U S A 104, 95299533.

10OA Khan , C Torrens , DE Noakes , (2005) Effects of pre-natal and early post-natal undernutrition on adult internal thoracic artery function. Eur J Cardiothorac Surg 28, 811815.

11C Torrens , TH Snelling , R Chau , (2009) Effects of pre- and periconceptional undernutrition on arterial function in adult female sheep are vascular bed dependent. Exp Physiol 94, 10241033.

12GS Gopalakrishnan , DS Gardner , SM Rhind , (2004) Programming of adult cardiovascular function after early maternal undernutrition in sheep. Am J Physiol Regul Integr Comp Physiol 287, R12R20.

14LT Skeggs , JR Kahn & NP Shumway (1956) The preparation and function of the hypertensin-converting enzyme. J Exp Med 103, 295299.

15S Higuchi , H Ohtsu , H Suzuki , (2007) Angiotensin II signal transduction through the AT1 receptor: novel insights into mechanisms and pathophysiology. Clin Sci (Lond) 112, 417428.

17PK Mehta & KK Griendling (2007) Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system. Am J Physiol Cell Physiol 292, C82C97.

18R Lucius , S Gallinat , S Busche , (1999) Beyond blood pressure: new roles for angiotensin II. Cell Mol Life Sci 56, 10081019.

19T Unger (2002) The role of the renin–angiotensin system in the development of cardiovascular disease. Am J Cardiol 89, 3A9A.

20SC Langley-Evans & AA Jackson (1995) Captopril normalises systolic blood pressure in rats with hypertension induced by fetal exposure to maternal low protein diets. Comp Biochem Physiol A Physiol 110, 223228.

21RC Sherman & SC Langley-Evans (2000) Antihypertensive treatment in early postnatal life modulates prenatal dietary influences upon blood pressure in the rat. Clin Sci (Lond) 98, 269275.

23VM Vehaskari , T Stewart , D Lafont , (2004) Kidney angiotensin and angiotensin receptor expression in prenatally programmed hypertension. Am J Physiol Renal Physiol 287, F262F267.

24C Bertram , AR Trowern , N Copin , (2001) The maternal diet during pregnancy programs altered expression of the glucocorticoid receptor and type 2 11β-hydroxysteroid dehydrogenase: potential molecular mechanisms underlying the programming of hypertension in utero. Endocrinology 142, 28412853.

25R Fernandez-Gonzalez , P Moreira , A Bilbao , (2004) Long-term effect of in vitro culture of mouse embryos with serum on mRNA expression of imprinting genes, development, and behavior. Proc Natl Acad Sci U S A 101, 58805885.

26WY Kwong , AE Wild , P Roberts , (2000) Maternal undernutrition during the preimplantation period of rat development causes blastocyst abnormalities and programming of postnatal hypertension. Development 127, 41954202.

27KD Sinclair , C Allegrucci , R Singh , (2007) DNA methylation, insulin resistance, and blood pressure in offspring determined by maternal periconceptional B vitamin and methionine status. Proc Natl Acad Sci U S A 104, 1935119356.

28AJ Watkins , D Platt , T Papenbrock , (2007) Mouse embryo culture induces changes in postnatal phenotype including raised systolic blood pressure. Proc Natl Acad Sci U S A 104, 54495454.

29AJ Watkins , E Ursell , R Panton , (2008) Adaptive responses by mouse early embryos to maternal diet protect fetal growth but predispose to adult onset disease. Biol Reprod 78, 299306.

30M Ceelen , MM van Weissenbruch , JP Vermeiden , (2008) Cardiometabolic differences in children born after in vitro fertilization: follow-up study. J Clin Endocrinol Metab 93, 16821688.

31JA Rooke , TG McEvoy , CJ Ashworth , (2007) Ovine fetal development is more sensitive to perturbation by the presence of serum in embryo culture before rather than after compaction. Theriogenology 67, 639647.

32DL Zander , JG Thompson & M Lane (2006) Perturbations in mouse embryo development and viability caused by ammonium are more severe after exposure at the cleavage stages. Biol Reprod 74, 288294.

33D Feil , M Lane , CT Roberts , (2006) Effect of culturing mouse embryos under different oxygen concentrations on subsequent fetal and placental development. J Physiol 572, 8796.

34WY Kwong , DJ Miller , E Ursell , (2006) Imprinted gene expression in the rat embryo-fetal axis is altered in response to periconceptional maternal low protein diet. Reproduction 132, 265277.

35WY Kwong , DJ Miller , AP Wilkins , (2007) Maternal low protein diet restricted to the preimplantation period induces a gender-specific change on hepatic gene expression in rat fetuses. Mol Reprod Dev 74, 4856.

36AJ Watkins , A Wilkins , C Cunningham , (2008) Low protein diet fed exclusively during mouse oocyte maturation leads to behavioural and cardiovascular abnormalities in offspring. J Physiol 586, 22312244.

37MY Liu , Y Hattori , M Fukao , (2001) Alterations in EDHF-mediated hyperpolarization and relaxation in mesenteric arteries of female rats in long-term deficiency of oestrogen and during oestrus cycle. Br J Pharmacol 132, 10351046.

38JF Bertram (1995) Analyzing renal glomeruli with the new stereology. Int Rev Cytol 161, 111172.

39J Vandesompele , K De Preter , F Pattyn , (2002) Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol 3, RESEARCH0034.

40A Watkins , A Wilkins , C Osmond , (2006) The influence of mouse Ped gene expression on postnatal development. J Physiol 571, 211220.

41WY Kwong , C Osmond & TP Fleming (2004) Support for Barker hypothesis upheld in rat model of maternal undernutrition during the preimplantation period: application of integrated ‘random effects’ statistical model. Reprod Biomed Online 8, 574576.

42D Lamireau , AM Nuyt , X Hou , (2002) Altered vascular function in fetal programming of hypertension. Stroke 33, 29922998.

43AM Samuelsson , PA Matthews , M Argenton , (2008) Diet-induced obesity in female mice leads to offspring hyperphagia, adiposity, hypertension, and insulin resistance: a novel murine model of developmental programming. Hypertension 51, 383392.

44WJ Tang & AG Gilman (1992) Adenylyl cyclases. Cell 70, 869872.

45M Longo , V Jain , YP Vedernikov , (2005) Fetal origins of adult vascular dysfunction in mice lacking endothelial nitric oxide synthase. Am J Physiol Regul Integr Comp Physiol 288, R1114R1121.

46E Delpy , H Coste & AC Gouville (1996) Effects of cyclic GMP elevation on isoprenaline-induced increase in cyclic AMP and relaxation in rat aortic smooth muscle: role of phosphodiesterase. Br J Pharmacol 119, 471478.

47S Kagota , A Tamashiro , Y Yamaguchi , (2001) Downregulation of vascular soluble guanylate cyclase induced by high salt intake in spontaneously hypertensive rats. Br J Pharmacol 134, 737744.

49H Ruetten , U Zabel , W Linz , (1999) Downregulation of soluble guanylyl cyclase in young and aging spontaneously hypertensive rats. Circ Res 85, 534541.

50CR Esther , EM Marino , TE Howard , (1997) The critical role of tissue angiotensin-converting enzyme as revealed by gene targeting in mice. J Clin Invest 99, 23752385.

51JD Klein , D Le Quach , JM Cole , (2002) Impaired urine concentration and absence of tissue ACE: involvement of medullary transport proteins. Am J Physiol Renal Physiol 283, F517F524.

52T Forrester , N McFarlane-Anderson , FI Bennett , (1997) The angiotensin converting enzyme and blood pressure in Jamaicans. Am J Hypertens 10, 519524.

53F Nystrom , BE Karlberg & KP Ohman (1997) Serum angiotensin-converting enzyme activity correlates positively with plasma angiotensin II: a population-based study of ambulatory blood pressure and the renin–angiotensin system. J Hum Hypertens 11, 301306.

54AJ Forhead , F Broughton Pipkin & AL Fowden (2000) Effect of cortisol on blood pressure and the renin–angiotensin system in fetal sheep during late gestation. J Physiol 526, 167176.

55SC Langley-Evans , SJ Welham & AA Jackson (1999) Fetal exposure to a maternal low protein diet impairs nephrogenesis and promotes hypertension in the rat. Life Sci 64, 965974.

56CC Hoppe , RG Evans , JF Bertram , (2007) Effects of dietary protein restriction on nephron number in the mouse. Am J Physiol Regul Integr Comp Physiol 292, R1768R1774.

57R Manalich , L Reyes , M Herrera , (2000) Relationship between weight at birth and the number and size of renal glomeruli in humans: a histomorphometric study. Kidney Int 58, 770773.

58LA Ortiz , A Quan , F Zarzar , (2003) Prenatal dexamethasone programs hypertension and renal injury in the rat. Hypertension 41, 328334.

59P Pladys , F Sennlaub , S Brault , (2005) Microvascular rarefaction and decreased angiogenesis in rats with fetal programming of hypertension associated with exposure to a low-protein diet in utero. Am J Physiol Regul Integr Comp Physiol 289, R1580R1588.

60LL Woods , JR Ingelfinger & R Rasch (2005) Modest maternal protein restriction fails to program adult hypertension in female rats. Am J Physiol Regul Integr Comp Physiol 289, R1131R1136.

61KM Moritz & EM Wintour (1999) Functional development of the meso- and metanephros. Pediatr Nephrol 13, 171178.

62E Angiolini , A Fowden , P Coan , (2006) Regulation of placental efficiency for nutrient transport by imprinted genes. Placenta 27, S98S102.

63FM Smith , AS Garfield & A Ward (2006) Regulation of growth and metabolism by imprinted genes. Cytogenet Genome Res 113, 279291.

Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

British Journal of Nutrition
  • ISSN: 0007-1145
  • EISSN: 1475-2662
  • URL: /core/journals/british-journal-of-nutrition
Please enter your name
Please enter a valid email address
Who would you like to send this to? *