Skip to main content Accessibility help

Protein restriction during pregnancy induces hypertension in adult female rat offspring – influence of oestradiol

  • K. Sathishkumar (a1), Rebekah Elkins (a1), Uma Yallampalli (a1) and Chandra Yallampalli (a1)


We previously reported that gestational dietary protein restriction in rats causes sex-related differences in development of blood pressure (BP) in the offspring, which is more pronounced in males than in females. As such effects may depend on sex hormones, we investigated the role of oestradiol in the development of hypertension in female offspring of protein-restricted dams. Female offspring of pregnant rats fed normal (20 %) or protein-restricted (6 %) casein diets throughout pregnancy were kept either intact, ovariectomised or ovariectomised with oestradiol supplementation. BP, Plasma oestradiol and testosterone levels, and vascular oestrogen receptor (ER) were examined. BP was significantly higher and plasma oestradiol levels were significantly lower ( − 34 %) in intact protein-restricted female offspring compared to corresponding controls. Further decrease in oestradiol levels by ovariectomy exacerbated hypertension in the protein-restricted females, with an earlier onset and more prominent elevation in BP compared to controls. Oestradiol supplementation in ovariectomised protein-restricted females significantly reversed ovariectomy-induced hypertension but did not normalise BP to control levels. The hypertensive protein-restricted females have reduced vascular ERα expression that was unaffected by ovariectomy or oestradiol replacement. In addition, testosterone levels were significantly higher by 2·4-, 3·4- and 2·8-fold in intact, ovariectomised and oestradiol-replaced protein-restricted females compared to corresponding controls. The present data show that: (1) hypertension in protein-restricted adult female offspring is associated with reduced plasma oestradiol levels; (2) oestradiol protects and limits the severity of hypertension in protein-restricted females and contributes to sexual dimorphism; (3) oestradiol replacement fails to completely reverse hypertension, which may be related to limited availability of vascular ERα receptors and/or increased circulating testosterone levels.

  • 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. 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.

      Protein restriction during pregnancy induces hypertension in adult female rat offspring – influence of oestradiol
      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 <service> account. Find out more about sending content to Dropbox.

      Protein restriction during pregnancy induces hypertension in adult female rat offspring – influence of oestradiol
      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 <service> account. Find out more about sending content to Google Drive.

      Protein restriction during pregnancy induces hypertension in adult female rat offspring – influence of oestradiol
      Available formats


Corresponding author

*Corresponding author: Dr C. Yallampalli, fax +1 409 772 2261, email


Hide All
1 Barker, DJ & Osmond, C (1986) Infant mortality, childhood nutrition, and ischaemic heart disease in England and Wales. Lancet i, 10771081.
2 Barker, DJ, Shiell, AW, Barker, ME, et al. (2000) Growth in utero and blood pressure levels in the next generation. J Hypertens 18, 843846.
3 Hemmings, DG, Williams, SJ & Davidge, ST (2005) Increased myogenic tone in 7-month-old adult male but not female offspring from rat dams exposed to hypoxia during pregnancy. Am J Physiol Heart Circ Physiol 289, H674H682.
4 Ojeda, NB, Grigore, D, Robertson, , et al. (2007) Estrogen protects against increased blood pressure in postpubertal female growth restricted offspring. Hypertension 50, 679685.
5 Woods, LL, Weeks, DA & Rasch, R (2004) Programming of adult blood pressure by maternal protein restriction: role of nephrogenesis. Kidney Int 65, 13391348.
6 Gangula, PR, Reed, L & Yallampalli, C (2005) Antihypertensive effects of flutamide in rats that are exposed to a low-protein diet in utero. Am J Obstet Gynecol 192, 952960.
7 Langley, SC & Jackson, AA (1994) Increased systolic blood pressure in adult rats induced by fetal exposure to maternal low protein diets. Clin Sci (Lond) 86, 217222.
8 Sathishkumar, K, Elkins, R, Yallampalli, U, et al. (2008) Protein restriction during pregnancy induces hypertension and impairs endothelium-dependent vascular function in adult female offspring. J Vasc Res 46, 229239.
9 Alexander, BT (2006) Fetal programming of hypertension. Am J Physiol Regul Integr Comp Physiol 290, R1R10.
10 Moritz, KM & Cuhen-McEwen, LA (2006) Kidney development and fetal programming. Early Life Origins of Health and Disease. Adv Exp Med Biol 573, 130144.
11 Reckelhoff, JF (2001) Gender differences in the regulation of blood pressure. Hypertension 37, 11991208.
12 Woods, LL & Weeks, DA (2005) Prenatal programming of adult blood pressure: role of maternal corticosteroids. Am J Physiol Regul Integr Comp Physiol 289, R955R962.
13 Woods, LL, Ingelfinger, JR & Rasch, R (2005) Modest maternal protein restriction fails to program adult hypertension in female rats. Am J Physiol Regul Integr Comp Physiol 289, R1131R1136.
14 Hinojosa-Laborde, C, Lange, DL & Haywood, JR (2000) Role of female sex hormones in the development and reversal of Dahl hypertension. Hypertension 35, 484489.
15 Hinojosa-Laborde, C, Craig, T, Zheng, W, et al. (2004) Ovariectomy augments hypertension in aging female Dahl salt-sensitive rats. Hypertension 44, 405409.
16 Oparil, S (1999) Corcocran Memorial Lecture. Hormones and vasoprotection. Hypertension 33, 170176.
17 Chappell, MC, Yamaleyeva, LM & Westwood, BM (2006) Estrogen and salt sensitivity in the female mRen(2).Lewis rat. Am J Physiol Regul Integr Comp Physiol 291, R1557R1563.
18 Franco, MC, Arruda, RM, Dantas, AP, et al. (2002) Intrauterine undernutrition: expression and activity of the endothelial nitric oxide synthase in male and female adult offspring. Cardiovasc Res 56, 145153.
19 Ross, GR, Chauhan, M, Gangula, PR, et al. (2006) Female sex steroids increase adrenomedullin-induced vasodilation by increasing the expression of adrenomedullin2 receptor components in rat mesenteric artery. Endocrinology 147, 389396.
20 Gabriel, SM, Roncancio, JR & Ruiz, NS (1992) Growth hormone pulsatility and the endocrine milieu during sexual maturation in male and female rats. Neuroendocrinology 56, 619625.
21 Smith, MS, Freeman, ME & Neill, JD (1975) The control of progesterone secretion during the estrous cycle and early pseudopregnancy in the rat: prolactin, gonadotropin and steroid levels associated with rescue of the corpus luteum of pseudopregnancy. Endocrinology 96, 219226.
22 Wells, CC, Riazi, S, Mankhey, RW, et al. (2005) Diabetic nephropathy is associated with decreased circulating estradiol levels and imbalance in the expression of renal estrogen receptors. Gend Med 2, 227237.
23 Daugherty, A, Rateri, D, Hong, L, et al. (2009) Measuring blood pressure in mice using volume pressure recording, a tail-cuff method. J Vis Exp 27, 12911292.
24 Woods, LL, Ingelfinger, JR, Nyengaard, JR, et al. (2001) Maternal protein restriction suppresses the newborn renin–angiotensin system and programs adult hypertension in rats. Pediatr Res 49, 460467.
25 Musha, Y, Itoh, S, Hanson, MA, et al. (2006) Does estrogen affect the development of abnormal vascular function in offspring of rats fed a low-protein diet in pregnancy? Pediatr Res 59, 784789.
26 Leonhardt, M, Lesage, J, Croix, D, et al. (2003) Effects of perinatal maternal food restriction on pituitary–gonadal axis and plasma leptin level in rat pup at birth and weaning and on timing of puberty. Biol Reprod 68, 390400.
27 Guzman, C, Cabrera, R, Cardenas, M, et al. (2006) Protein restriction during fetal and neonatal development in the rat alters reproductive function and accelerates reproductive ageing in female progeny. J Physiol 572, 97108.
28 da Silva, FT, de Bittencourt, BF, Sampaio, FJ, et al. (2010) Maternal malnutrition during lactation affects folliculogenesis, gonadotropins, and leptin receptors in adult rats. Nutrition 26, 10001007.
29 Hsueh, AJ & Erickson, GF (1978) Glucocorticoid inhibition of FSH-induced estrogen production in cultured rat granulosa cells. Steroids 32, 639648.
30 Verhoeven, G & Cailleau, J (1988) Prolonged exposure to androgens suppresses follicle-stimulating hormone-induced aromatase activity in rat Sertoli cell cultures. Mol Cell Endocrinol 57, 6167.
31 Ricchiuti, V, Lian, CG, Oestreicher, EM, et al. (2009) Estradiol increases angiotensin II type 1 receptor in hearts of ovariectomized rats. J Endocrinol 200, 7584.
32 Sokol, RZ, Okuda, H, Stanczyk, FZ, et al. (1999) Normative reproductive indices for male and female adult Sprague–Dawley rats. Contraception 59, 203207.
33 Bolego, C, Cignarella, A, Sanvito, P, et al. (2005) The acute estrogenic dilation of rat aorta is mediated solely by selective estrogen receptor-alpha agonists and is abolished by estrogen deprivation. J Pharmacol Exp Ther 313, 12031208.
34 Pinna, C, Cignarella, A, Sanvito, P, et al. (2008) Prolonged ovarian hormone deprivation impairs the protective vascular actions of estrogen receptor alpha agonists. Hypertension 51, 12101217.
35 Bolego, C, Vegeto, E, Pinna, C, et al. (2006) Selective agonists of estrogen receptor isoforms: new perspectives for cardiovascular disease. Arterioscler Thromb Vasc Biol 26, 21922199.
36 Torrens, C, Brawley, L, Barker, AC, et al. (2003) Maternal protein restriction in the rat impairs resistance artery but not conduit artery function in pregnant offspring. J Physiol 547, 7784.
37 Thornton, MJ, Nelson, LD, Taylor, AH, et al. (2006) The modulation of aromatase and estrogen receptor alpha in cultured human dermal papilla cells by dexamethasone: a novel mechanism for selective action of estrogen via estrogen receptor beta? J Invest Dermatol 126, 20102018.
38 Langley-Evans, SC & Nwagwu, M (1998) Impaired growth and increased glucocorticoid-sensitive enzyme activities in tissues of rat fetuses exposed to maternal low protein diets. Life Sci 63, 605615.
39 Bertram, C, Trowern, AR, Copin, N, et al. (2001) The maternal diet during pregnancy programs altered expression of the glucocorticoid receptor and type 2 11beta-hydroxysteroid dehydrogenase: potential molecular mechanisms underlying the programming of hypertension in utero. Endocrinology 142, 28412853.
40 Langley-Evans, SC, Gardner, DS & Jackson, AA (1996) Maternal protein restriction influences the programming of the rat hypothalamic–pituitary–adrenal axis. J Nutr 126, 15781585.
41 MacLennan, NK, James, SJ, Melnyk, S, et al. (2004) Uteroplacental insufficiency alters DNA methylation, one-carbon metabolism, and histone acetylation in IUGR rats. Physiol Genomics 18, 4350.
42 Edelmann, MN & Auger, AP (2011) Epigenetic impact of simulated maternal grooming on estrogen receptor alpha within the developing amygdala. Brain Behav Immun (In the Press).
43 Weiner, CP, Lizasoain, I, Baylis, SA, et al. (1994) Induction of calcium-dependent nitric oxide synthases by sex hormones. Proc Natl Acad Sci U S A 91, 52125216.
44 Manson, JE, Hsia, J, Johnson, KC, et al. (2003) Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med 349, 523534.
45 Prelevic, GM, Kwong, P, Byrne, DJ, et al. (2002) A cross-sectional study of the effects of hormone replacement therapy on the cardiovascular disease risk profile in healthy postmenopausal women. Fertil Steril 77, 945951.
46 Chen, YF & Meng, QC (1991) Sexual dimorphism of blood pressure in spontaneously hypertensive rats is androgen dependent. Life Sci 48, 8596.
47 Reckelhoff, JF, Zhang, H & Granger, JP (1998) Testosterone exacerbates hypertension and reduces pressure-natriuresis in male spontaneously hypertensive rats. Hypertension 31, 435439.
48 Dahlgren, J, Nilsson, C, Jennische, E, et al. (2001) Prenatal cytokine exposure results in obesity and gender-specific programming. Am J Physiol Endocrinol Metab 281, E326E334.
49 Gotz, F, Dorner, G, Malz, U, et al. (1993) Short- and long-term effects of perinatal interleukin-1 beta-application in rats. Neuroendocrinology 58, 344351.
50 Flores, A, Rodriguez, JO, Palafox, MT, et al. (2006) The acute asymmetric effects of hemiovariectomy on testosterone secretion vary along the estrous cycle. The participation of the cholinergic system. Reprod Biol Endocrinol 4, 11.
51 Labrie, F, Luu-The, V, Labrie, C, et al. (2000) Intracrinology and the skin. Horm Res 54, 218229.
52 Quinkler, M, Sinha, B, Tomlinson, JW, et al. (2004) Androgen generation in adipose tissue in women with simple obesity – a site-specific role for 17beta-hydroxysteroid dehydrogenase type 5. J Endocrinol 183, 331342.
53 Iliescu, R, Cucchiarelli, VE, Yanes, LL, et al. (2007) Impact of androgen-induced oxidative stress on hypertension in male SHR. Am J Physiol Regul Integr Comp Physiol 292, R731R735.
54 Yanes, LL, Romero, DG, Cucchiarelli, VE, et al. (2005) Role of endothelin in mediating postmenopausal hypertension in a rat model. Am J Physiol Regul Integr Comp Physiol 288, R229R233.
55 Elliot, SJ, Berho, M, Korach, K, et al. (2007) Gender-specific effects of endogenous testosterone: female alpha-estrogen receptor-deficient C57Bl/6J mice develop glomerulosclerosis. Kidney Int 72, 464472.
56 Zambrano, E, Rodriguez-Gonzalez, GL, Guzman, C, et al. (2005) A maternal low protein diet during pregnancy and lactation in the rat impairs male reproductive development. J Physiol 563, 275284.



Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed