Skip to main content Accessibility help
  • Print publication year: 2006
  • Online publication date: August 2009

21 - The role of vascular dysfunction in developmental origins of health and disease: evidence from human and animal studies



Early studies in population cohorts proposed that perturbation of the environment in utero and in early life gives rise to marked and permanent alteration in offspring cardiovascular homeostasis, leading to increased risk of cardiovascular and metabolic disease in later life (reviewed in this volume). Clinical outcomes focused on the incidence of heart disease and hypertension in relation to birthweight, with little detailed investigation of other parameters of cardiovascular risk or outcome. More recent studies have given insight into underlying aetiological pathways, and the development of the different animal models of developmental plasticity has provided an opportunity to assess parameters of cardiovascular function at a depth which is not feasible, or indeed practicable, in humans.

The mechanisms contributing to cardiovascular homeostasis are complex and interwoven; they range from central control of the heart rate and vascular tone to paracrine, autocrine and genomic influences on the vascular smooth muscle and function of the endothelium. Fluid and volume homeostatic pathways, as well as the intricacy of haemostatic control, also contribute to the status quo. The complexity is such that common disorders such as essential hypertension remain poorly understood despite decades of research. The scientist wishing to investigate developmental programming of, for example, metabolic syndrome faces a bewildering choice of avenues to explore. Without a firm understanding of the early aetiology of hypertension or of insulin resistance, he or she has little choice but to follow the well-trodden paths which characterise research into these disorders in humans.

Related content

Powered by UNSILO
Ahokas, R. A., Reynolds, S. L., Anderson, G. D. and Lipshitz, J. (1984). Maternal organ distribution of cardiac output in the diet-restricted pregnant rat. J. Nutr., 114, 2262–8.
Anderson, T. J., Uehata, A., Gerhard, M. al. (1995). Close relation of endothelial function in the human coronary and peripheral circulations. J. Am. Coll. Cardiol., 26, 1235–41.
Armitage, J. A., Khan, I. Y., Taylor, P. D., Nathanielsz, P. W. and Poston, L. (2004a). Developmental programming of metabolic syndrome by maternal nutritional imbalance: how strong is the evidence from experimental models in animals?J. Physiol., 561, 355–77.
Armitage, J. A., Jensen, R., Taylor, P. D. and Poston, L. (2004b). Exposure to a high fat diet during gestation and weaning results in reduced elasticity and endothelial function as well as altered gene expression and fatty acid content of rat aorta. J. Soc. Gynecol. Investig., 11, 183A.
Armitage, J. A., Ishibashi, A., Taylor, P. D. and Poston, L. (2004c). Developmental programming of aortic dysfunction by maternal fat-feeding does not persist to the second generation. J. Physiol., 565P, C165.
Barja-Fidalgo, C., Souza, E. P., Silva, S. al. (2003). Impairment of inflammatory response in adult rats submitted to maternal undernutrition during early lactation: role of insulin and glucocorticoid. Inflamm. Res., 52, 470–6.
Berry, C. L. and Looker, T. (1973). An alteration in the chemical structure of the aortic wall induced by a finite period of growth inhibition. J. Anat., 114, 83–94.
Black, H. R. (2004). The paradigm has shifted to systolic blood pressure. J. Hum. Hypertens., 18, S3–7.
Boo, Y. C. and Jo, H. (2003). Flow-dependent regulation of endothelial nitric oxide synthase: role of protein kinases. Am. J. Physiol. Cell. Physiol., 285, C499–508.
Brawley, L., Itoh, S., Torrens, C., Barker, A., Bertram, C., Poston, L. and Hanson, M. (2003). Dietary protein restriction in pregnancy induces hypertension and vascular defects in rat male offspring. Pediatr. Res., 54, 83–90.
Busse, R., Edwards, G., Feletou, M., Fleming, I., Vanhoutte, P. M. and Weston, A. H. (2002). EDHF: bringing the concepts together. Trends Pharmacol. Sci., 23, 374–80.
Byberg, L., McKeigue, P. M., Zethelius, B. and Lithell, H. O. (2000). Birth weight and the insulin resistance syndrome: association of low birth weight with truncal obesity and raised plasminogen activator inhibitor-1 but not with abdominal obesity or plasma lipid disturbances. Diabetologia, 43, 54–60.
Chan, N. and Vallance, P. (2002). Nitric oxide. In An Introduction to Vascular Biology (ed. Hunt, B., Poston, L., Schachter, M. and Halliday, A.). Cambridge: Cambridge University Press, pp. 216–58.
Dance, C. S., Brawley, L., Dunn, R. L., Poston, L., Jackson, A. A. and Hanson, M. A. (2003). Folate supplementation of a protein restricted diet during pregnancy: restoration of vascular dysfunction in small mesenteric arteries of female adult rat offspring. Pediatr. Res., 53, 19A.
Dandrea, J., Cooper, S., Ramsay, M. al. (2002). The effects of pregnancy and maternal nutrition on the maternal renin–angiotensin system in sheep. Exp. Physiol., 87, 353–9.
Drake, A. J., Walker, B. R. and Seckl, J. R. (2005). Intergenerational consequences of fetal programming by in utero exposure to glucocorticoids in rats. Am. J. Physiol. Regul. Integr. Comp. Physiol., 288, R34–8.
Edwards, L. J. and McMillen, I. C. (2001). Maternal undernutrition increases arterial blood pressure in the sheep fetus during late gestation. J. Physiol., 533, 561–70.
Edwards, L. J., Bryce, A. E., Coulter, C. L. and McMillen, I. C. (2002). Maternal undernutrition throughout pregnancy increases adrenocorticotrophin receptor and steroidogenic acute regulatory protein gene expression in the adrenal gland of twin fetal sheep during late gestation. Mol. Cell. Endocrinol., 196, 1–10.
Franco, M. C., Arruda, R. M., Dantas, A. al. (2002). Intrauterine undernutrition: expression and activity of the endothelial nitric oxide synthase in male and female adult offspring. Cardiovasc. Res., 56, 145–53.
Franco, M. C., Akamine, E. H., Di Marco, G. al. (2003). NADPH oxidase and enhanced superoxide generation in intrauterine undernourished rats: involvement of the renin–angiotensin system. Cardiovasc. Res., 59, 767–75.
Franco, M. C., Akamine, E. H., Fortes, Z. al. (2004). Tetrahydrobiopterin improves endothelial dysfunction and vascular oxidative stress in microvessels of intrauterine undernourished rats. J. Physiol., 558, 239–48.
Gardner, D. S., Pearce, S., Dandrea, al. (2004). Peri-implantation undernutrition programs blunted angio-tensin II evoked baroreflex responses in young adult sheep. Hypertension, 43, 1290–6.
Ghosh, P., Bitsanis, D., Ghebremeskel, K., Crawford, M. A. and Poston, L. (2001). Abnormal fatty acid composition and small artery function in offspring of rats fed a high fat diet in pregnancy. J. Physiol., 533, 815–22.
Giussani, D. A., Spencer, J. A., Moore, P. J., Bennet, L. and Hanson, M. A. (1993). Afferent and efferent components of the cardiovascular reflex responses to acute hypoxia in term fetal sheep. J. Physiol., 461, 431–49.
Gluckman, P. D. and Hanson, M. A. (in press). Endothelial dysfunction and cardiovascular disease: the role of PARs. Heart.
Goh, K. L., Shore, A. C., Quinn, M. and Tooke, J. E. (2001). Impaired microvascular vasodilatory function in 3-month-old infants of low birth weight. Diabetes Care, 24, 1102–7.
Goodfellow, J., Bellamy, N. F., Gorman, S. al. (1998). Endothelial function is impaired in fit young adults of low birthweight. Cardiovasc. Res., 40, 600–6.
Gopalakrishnan, G. S., Gardner, D. S., Rhind, S. al. (2004). Programming of adult cardiovascular function after early maternal undernutrition in sheep. Am. J. Physiol. Regul. Integr. Comp. Physiol., 287, R12–20.
Goyal, H. O., Robateau, A., Braden, T. D., Williams, C. S., Srivastava, K. K. and Ali, K. (2003). Neonatal estrogen exposure of male rats alters reproductive functions at adulthood. Biol. Reprod., 68, 2081–91.
Guo, F. and Jen, K. L. (1995). High-fat feeding during pregnancy and lactation affects offspring metabolism in rats. Physiol. Behav., 57, 681–6.
Halcox, J. P. J., Schenke, W. H., Zalos, al. (2002). Prognostic value of coronary vascular endothelial dysfunction. Circulation, 106, 653–8.
Hanson, M. A., Hawkins, P., Ozaki, T. et al. (1999). Effects of experimental dietary manipulation during early pregnancy on the cardiovascular and endocrine function in fetal sheep and young lambs. In Fetal Programming: Consequences for Health in Later Life (ed. Barker, D. J. P. and Wheeler, T.). London: RCOG Press, pp. 365–73.
Hawkins, P., Steyn, C., McGarrigle, H. al. (1999). Effect of maternal nutrient restriction in early gestation on development of the hypothalamic–pituitary–adrenal axis in fetal sheep at 0.8–0.9 of gestation. J. Endocrinol., 163, 553–61.
Hawkins, P., Steyn, C., Ozaki, T., Saito, T., Noakes, D. E. and Hanson, M. A. (2000a). Effect of maternal undernutrition in early gestation on ovine fetal blood pressure and cardiovascular reflexes. Am. J. Physiol. Regul. Integr. Comp. Physiol., 279, R340–8.
Hawkins, P., Steyn, C., McGarrigle, H. al. (2000b). Cardiovascular and hypothalamic–pituitary–adrenal axis development in late gestation fetal sheep and young lambs following modest maternal nutrient restriction in early gestation. Reprod. Fertil. Dev., 12, 443–56.
Holemans, K., Gerber, R., Meurrens, K., De, Clerck, F., Poston, L. and Assche, F. A. (1999). Maternal food restriction in the second half of pregnancy affects vascular function but not blood pressure of rat female offspring. Br. J. Nutr., 81, 73–9.
Hsueh, W. A., Lyon, C. J. and Quinones, M. J. (2004). Insulin resistance and endothelium. Am. J. Med., 117, 109–17.
Hunt, B. J. and Jurd, K. M. (2002). The endothelium in health and disease. In An Introduction to Vascular Biology (ed. Hunt, B., Poston, L., Schachter, M. and Halliday, A.). Cambridge: Cambridge University Press, pp. 186–215.
Ijzerman, R. G., Weissenbruch, M. M., Voordouw, J. al. (2002). The association between birth weight and capillary recruitment is independent of blood pressure and insulin sensitivity: a study in prepurbertal children. J. Hypertens., 20, 1957–63.
Ijzerman, R. G., Stehouwer, C. D., Geus, E. J., Kluft, C. and Boomsma, D. I. (2003). The association between birth weight and plasma fibrinogen is abolished after the elimination of genetic influencesJ. Thromb. Haemost., 1, 239–42.
Intengan, H. D., Thibault, G., Li, J. S. and Schiffrin, E. L. (1999). Resistance artery mechanics, structure, and extracellular components in spontaneously hypertensive rats: effects of angiotensin receptor antagonism and converting enzyme inhibition. Circulation, 100, 2267–75.
Irving, R. J., Shore, A. C., Belton, N. R., Elton, R. A., Webb, D. J. and Walker, B. R. (2004). Low birth weight predicts higher blood pressure but not dermal capillary density in two populations. Hypertension, 43, 610–13.
Kaati, G., Bygren, L. O. and Edvinsson, S. (2002). Cardiovascular and diabetes mortality determined by nutrition during parents' and grandparents' slow growth period. Eur. J. Hum. Genet., 10, 682–8.
Karnik, H. B., Sonawane, B. R., Adkins, J. S. and Mohla, S. (1989). High dietary fat feeding during perinatal development of rats alters hepatic drug metabolism of progeny. Dev. Pharmacol. Ther., 14, 135–40.
Khan, I. Y., Taylor, P. D., Dekou, al. (2003). Gender-linked hypertension in offspring of lard-fed pregnant rats. Hypertension, 41, 168–75.
Khan, I. Y., Dekou, V., Hanson, M., Poston, L. and Taylor, P. (2004). Predictive adaptive responses to maternal high fat diet prevent endothelial dysfunction but not hypertension in adult rat offspring. Circulation, 110, 1097–102.
Khan, I. Y., Dekou, V., Douglas, al. (2005). A high-fat diet during rat pregnancy or suckling induces cardiovascular dysfunction in adult offspring. Am. J. Physiol. Regul. Integr. Comp. Physiol., 288, R127–33.
Kind, K. L., Simonetta, G., Clifton, P. M., Robinson, J. S. and Owens, J. A. (2002). Effect of maternal feed restriction on blood pressure in the adult guinea pig. Exp. Physiol., 87, 469–77.
Kind, K. L., Clifton, P. M., Grant, P. al. (2003). Effect of maternal feed restriction during pregnancy on glucose tolerance in the adult guinea pig. Am. J. Physiol. Regul. Integr. Comp. Physiol., 284, R140–52.
Kingwell, B. A. and Gatzka, C. D. (2002). Aterial stiffness and prediction of cardiovascular risk. J. Hypertens., 20, 2337–40.
Kumeran, K., Fall, C., Martyn, C. N., Vijayakumar, M., Stein, C. and Shier, R. (2000). Blood pressure, arterial compliance and left ventricular mass: no relation to small size at birth in south Indian adults. Heart, 83, 272–7.
Kwong, W. Y., Wild, A. E., Roberts, P., Willis, A. C. and Fleming, T. P. (2000). Maternal undernutrition during the preimplantation period of rat development causes blastocyst abnormalities and programming of postnatal hypertension. Development, 127, 4195–202.
Lamireau, D., Nuyt, A. M., Hou, al. (2002). Altered vascular function in fetal programming of hypertension. Stroke, 33, 2992–8.
Landmesser, U., Hornig, B. and Drexler, H. (2004). Endothelial function: a critical determinant in atherosclerosis?Circulation, 109, 27–33.
Langley, S. C. and Jackson, A. A. (1994). Increased systolic blood pressure in adult rats induced by fetal exposure to maternal low protein diets. Clin. Sci., 86, 217–22.
Langley-Evans, S. C. (1996). Intrauterine programming of hypertension in the rat: nutrient interactions. Comp. Biochem. Physiol. A Physiol., 114, 327–33.
Langley-Evans, S. C. and Jackson, A. A. (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, 223–8.
Langley-Evans, S. C., Welham, S. J. and Jackson, A. A. (1999). Fetal exposure to a maternal low protein diet impairs nephrogenesis and promotes hypertension in the rat. Life Sci., 64, 965–74.
Leeson, C. P., Whincupp, P. H., Cook, D. al. (1997). Flow-mediated dilatation in 9–11 year old children: the influence of intrauterine and childhood factors. Circulation, 96, 2233–8.
Leeson, C. P., Katternhorm, M., Morley, R., Lucas, A. and Deanfield, J. E. (2001a). Impact of low birthweight and cardiovascular risk factors on endothelial function in early adult life. Circulation, 103, 1264–8.
Leeson, C. P., Katternhorm, M., Deanfield, J. E. and Lucas, A. (2001b). Duration of breast feeding and arterial distensibility in early life: population based study. BMJ, 332, 643–7.
Lesage, J., Blondeau, B., Grino, M., Breant, B. and Dupouy, J. P. (2001). Maternal undernutrition during late gestation induces fetal overexposure to glucocorticoids and intrauterine growth retardation, and disturbs the hypothalamo-pituitary adrenal axis in the newborn rat. Endocrinology, 142, 1692–702.
Libby, P. (2002). Inflammation and atherosclerosis. Nature, 420, 868–74.
Lillycrop, K. A., Phillips, G. S., Jackson, A. A., Hanson, M. A. and Burdge, G. C. (2005). Dietary protein restriction of pregnant rats induces and folic acid supplementation prevents epigenetic modification of hepatic gene expression in the offspring. J. Nutr., 135, 1382–6.
Martin, H., Hu, J., Gennser, G. and Norman, M. (2000). Impaired endothelial function and increased carotid stiffness in 9-year old children with low birthweight. Circulation, 102, 2739–44.
Martyn, C. N. and Greenwald, S. E. (1997). Impaired synthesis of elastin in walls of aorta and large conduit arteries during early development as an initiating event in pathogenesis of systemic hypertension. Lancet, 350, 953–5.
Martyn, C. N., Meade, T. W., Stirling, Y. and Barker, D. J. P. (1995a). Plasma concentrations of fibrinogen and factor VII in adult life and their relation to intra-uterine growth. Br. J. Haematol., 89, 142–6.
Martyn, C. N., Barker, D. J. P., Jespersen, S., Greenwald, S., Osmond, C. and Berry, C. (1995b). Growth in utero, adult blood pressure, and arterial compliance. Br. Heart J., 73, 116–21.
McAllister, A. S., Atkinson, A. B., Johnston, G. D. and McCance, D. R. (1999). Relationship of endothelial function to birth weight in humans. Diabetes Care, 22, 2061–6.
McMullen, S., Gardner, D. S. and Langley-Evans, S. C. (2004). Prenatal programming of angiotensin II type 2 receptor expression in the rat. Br. J. Nutr., 91, 133–40.
McVeigh, G. E., Brennan, G. M., Johnston, G. al. (1992). Impaired endothelium-dependent and independent vasodilation in patients with type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia, 35, 771–6.
Meigs, J. B., Hu, F. B., Rifai, N. and Manson, J. E. (2004). Biomarkers of endothelial dysfunction and risk of type 2 diabetes mellitus. JAMA, 291, 1978–86.
Merezak, S., Reusens, B., Renard, al. (2004). Effect of maternal low-protein diet and taurine on the vulnerability of adult Wistar rat islets to cytokines. Diabetologia, 47, 669–75.
Molnar, J., Howe, D. C., Nijland, M. J. and Nathanielsz, P. W. (2003). Prenatal dexamethasone leads to both endothelial dysfunction and vasodilatory compensation in sheep. J. Physiol., 547, 61–6.
Montgomery, A. A., Ben-Sholmo, Y., McCarthy, A., Davies, D., Elwood, P. and Smith, G. D. (2000). Birth size and arterial compliance in young adults. Lancet, 355, 2136–7.
Morgan, H. D., Sutherland, H. G., Martin, D. I. and Whitelaw, E. (1999). Epigenetic inheritance at the agouti locus in the mouse. Nat. Genet., 23, 314–18.
Napoli, C., Witztum, J. L., Calara, F., Nigris, F. and Palinski, W. (2000). Maternal hypercholesterolemia enhances atherogenesis in normocholesterolemic rabbits, which is inhibited by antioxidant or lipid-lowering intervention during pregnancy: an experimental model of atherogenic mechanisms in human fetuses. Circ. Res., 87, 946–52.
Nishina, H., Green, L. R., McGarrigle, H. H., Noakes, D. E., Poston, L. and Hanson, M. A. (2003). Effect of nutritional restriction in early pregnancy on isolated femoral artery function in mid-gestation fetal sheep. J. Physiol., 553, 637–47.
Norman, J. F., and LeVeen, R. F. (2001). Maternal atherogenic diet in swine is protective against early atherosclerosis development in offspring consuming an atherogenic diet post-natally. Atherosclerosis, 157, 41–7.
Norman, M. and Martin, H. (2003). Preterm birth attenuates association between low birthweight and endothelial dysfunction. Circulation, 108, 996–1001.
Owens, G. K., Kumar, M. S. and Wamhoff, B. R. (2004). Molecular regulation of vascular smooth muscle cell differentiation in development and disease. Physiol. Rev., 84, 767–801.
Ozaki, T., Nishina, H., Hanson, M. A. and Poston, L. (2001). Dietary restriction in pregnant rats causes gender-related hypertension and vascular dysfunction in offspring. J. Physiol., 530, 141–52.
Palinski, W., Armiento, D' F. P., Witztum, J. al. (2001). Maternal hypercholesterolemia and treatment during pregnancy influence the long-term progression of atherosclerosis in offspring of rabbits. Circ. Res., 89, 991–6.
Panza, J. A., Casino, P. R., Kilcoyne, C. M. and Quyyumi, A. A. (1993). Role of endothelium-derived nitric oxide in the abnormal endothelium-dependent vascular relaxation of patients with essential hypertension. Circulation, 87, 1468–74.
Phillips, D. I. and Barker, D. J. P. (1997). Association between low birthweight and high resting pulse in adult life: is the sympathetic nervous system involved in programming the insulin resistance syndrome. Diabet. Med., 14, 673–7.
Rakyan, V. K., Chong, S., Champ, M. al. (2003). Transgenerational inheritance of epigenetic states at the murine AxinFu allele occurs after maternal and paternal transmission. Proc. Nat. Acad. Sci. USA, 100, 2538–43.
Rees, W. D., Hay, S. M., Brown, D. S., Antipatis, C. and Palmer, R. M. (2000). Maternal protein deficiency causes hypermethylation of DNA in the livers of rat fetuses. J. Nutr., 130, 1821–6.
Resnick, O. and Morgane, P. J. (1983). Animal models for small-for-gestational-age (SGA) neonates and infants-at-risk (IAR). Brain Res., 312, 221–5.
Rosso, P. and Kava, R. (1980). Effects of food restriction on cardiac ouput and blood flow to the uterus and placenta in the pregnant rat. J. Nutr., 110, 2350–4.
Rosso, P. and Streeter, M. R. (1979). Effects of food or protein restriction on plasma volume expansion in pregnant rats. J. Nutr., 109, 1887–92.
Ruijtenbeek, K., Noble, F. A., Janssen, G. al. (2000). Chronic hypoxia stimulates periarterial sympathetic nerve development in chicken embryo. Circulation, 102, 2892–7.
Ruijtenbeek, K., Kessels, L. C., De, Mey, J. G. and Blanco, C. E. (2003). Chronic moderate hypoxia and protein malnutrition both induce growth retardation, but have distinct effects on arterial endothelium-dependent reactivity in the chicken embryo. Pediatr. Res., 53, 573–9.
Sattar, N., McConnachie, A., Reilly, O' al. (2004). Inverse association between birth weight and C-reactive protein concentrations in the MIDSPAN Family Study. Arterioscler. Thromb. Vasc. Biol., 24, 583–7.
Sherman, R. C. and Langley-Evans, S. C. (2000). Antihypertensive treatment in early postnatal life modulates prenatal dietary influences upon blood pressure in the rat. Clin. Sci., 98, 269–75.
Siemelink, M., Verhoef, A., Dormans, J. A., Span, P. N. and Piersma, A. H. (2002). Dietary fatty acid composition during pregnancy and lactation in the rat programs growth and glucose metabolism in the offspring. Diabetologia, 45, 1397–403.
Simpson, S. J., Batley, R. and Raubenheimer, D. (2003). Geometric analysis of macronutrient intake in humans: the power of protein?Appetite 41, 123–40.
Singhal, A. and Lucas, A. (2004). Early origins of cardiovascular disease: is there a unifying hypothesis?Lancet, 363, 1642–5.
Singhal, A., Cole, T. J., Fewtrell, M. and Lucas, A. (2004a). Breastmilk feeding and lipoprotein profile in adolescents born preterm: follow-up of a prospective randomised study. Lancet, 15, 1571–8.
Singhal, A., Cole, T. J. and Fewtrell, M., Deanfield, J. and Lucas, A. (2004b). Is slower early growth beneficial for long term cardiovascular health?Circulation, 109, 1108–13.
Szmitko, P. E., Wang, C. H., Weisel, R. al. (2003a). New markers of inflammation and endothelial cell activation. Circulation, 108, 1917–23.
Szmitko, P. E., Wang, C. H., Weisel, R. D., Jeffries, G. A., Anderson, T. J. and Verma, S. (2003b). Biomarkers of vascular disease linking inflammation to endothelial activation. Circulation, 108, 2041–48.
Taylor, P. D., McConnell, J., Khan, I. al. (2004a). Impaired glucose homeostasis and mitochondrial abnormalities in offspring of rats fed a fat-rich diet in pregnancy. Am. J. Physiol. Regul. Integr. Comp. Physiol., 288, R134–9.
Taylor, P. D., Khan, I. Y., Hanson, M. A. and Poston, L. (2004b). Impaired EDHF-mediated vasodilatation in adult offspring of rats exposed to a fat-rich diet in pregnancy. J. Physiol., 558, 943–51.
Te Velde, S. J., Ferreira, I., Twisk, J. W., Stehouwer, C. D., Mechelen, W. and Kemper, H. C. (2004). Birthweight and arterial stiffness and blood pressure in adulthood: results from the Amsterdam Growth and Health Longitudinal Study. Int. J. Epidemiol., 33, 154–61.
Tonkiss, J., Trzcinska, M., Galler, J. R., Ruiz-Opazo, N. and Herrera, V. L. (1998). Prenatal malnutrition-induced changes in blood pressure: dissociation of stress and nonstress responses using radiotelemetry. Hypertension, 32, 108–14.
Torrens, C., Brawley, L., Dance, C. S, Itoh, S., Poston, L. and Hanson, M. A. (2002). First evidence for transgenerational vascular programming in the rat protein restriction model. J. Physiol., 543P, 41P.
Torrens, C., Brawley, L., Barker, A. C., Itoh, S., Poston, L. and Hanson, M. A. (2003). Maternal protein restriction in the rat impairs resistance artery but not conduit artery function in pregnant offspring. J. Physiol., 547, 77–84.
Vickers, M. H., Breier, B. H., Cutfield, W. S., Hofman, P. L. and Gluckman, P. D. (2000). Fetal origins of hyperphagia, obesity, and hypertension and postnatal amplification by hypercaloric nutrition. Am. J. Physiol. Endocrinol. Metab., 279, E83–7.
Wadsworth, R. M. (1990). Calcium and vascular reactivity in aging and hypertension. J. Hypertens., 8, 975–83.
Walker, B. R., McConnachie, A., Noon, J. P., Webb, D. J. and Watt, G. C. (1998). Contribution of parental blood pressures to association between low birth weight and adult high blood pressure: cross sectional study. BMJ, 316, 834–7.
Waterland, R. A. and Jirtle, R. L. (2004). Early nutrition, epigenetic changes at transposons and imprinted genes, and enhanced susceptibility to adult chronic diseases. Nutrition, 20, 63–8.
Woodall, S. M., Johnston, B. M., Breier, B. H. and Gluckman, P. D. (1996). Chronic maternal undernutrition in the rat leads to delayed postnatal growth and elevated blood pressure of offspring. Pediatr. Res., 40, 438–43.
Woods, L. L., Ingelfinger, J. R., Nyengaard, J. R. and Rasch, R. (2001). Maternal protein restriction suppresses the newborn renin–angiotensin system and programs adult hypertension in rats. Pediatr. Res., 49, 460–7.
Young, J. B., Kaufman, L. N., Saville, M. E. and Landsberg, L. (1985). Increased sympathetic nervous system activity in rats fed a low-protein diet. Am. J. Physiol., 248, R627–37.
Yu, H. I., Sheu, W. H., Lai, C. J., Lee, W. J. and Chen, Y. T. (2001). Endothelial dysfunction in type 2 diabetes mellitus subjects with peripheral artery disease. Int. J. Cardiol., 78, 19–25.