Increased myogenic tone in 7-month-old adult male but not female offspring from rat dams exposed to hypoxia during pregnancy

Abstract

Hemmings, D. G., S. J. Williams, and S. T. Davidge. 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: H674 -H682, 2005. First published April 15, 2005; doi:10.1152/ajpheart.00191.2005.-Intrauterine growth restriction (IUGR) increases the risk of cardiovascular disease later in life. Vascular dysfunction occurs in adult offspring from animal models of IUGR including maternal undernutrition, but the influence of reduced fetal oxygen supply on adult vascular function is unclear. Myogenic responses, essential for vascular tone regulation, have not been evaluated in these offspring. We hypothesized that 7-mo-old offspring from hypoxic (12% O 2; H) or nutrient-restricted (40% of control; NR) rat dams would show greater myogenic responses than their 4-mo-old littermates or control (C) offspring through impaired modulation by vasodilators. Growth restriction occurred in male H (P Ͻ 0.01), male NR (P Ͻ 0.01), and female NR (P Ͻ 0.02), but not female H, offspring. Myogenic responses in mesenteric arteries from males but not females were increased at 7 mo in H (P Ͻ 0.01) and NR (P Ͻ 0.05) vs. C offspring. There was less modulation of myogenic responses after inhibition of nitric oxide synthase (P Ͻ 0.05), prostaglandin H synthase (P Ͻ 0.005), or both enzymes (P Ͻ 0.001) in arteries from 7-mo male H vs. C offspring. Thus reduced vasodilator modulation may explain elevated myogenic responses in 7-mo male H offspring. In contrast, there was increased modulation of myogenic responses in arteries from 7-mo female H vs. C or NR offspring after inhibition of both enzymes (P Ͻ 0.05). Thus increased vasodilator modulation may maintain myogenic responses in female H offspring at control levels. In summary, vascular responses in adult offspring from adverse intrauterine environments are impaired in a genderspecific, age-dependent, and maternal insult-dependent manner, with males more profoundly affected. fetal programming; undernutrition; nitric oxide; vascular function; gender EPIDEMIOLOGIC STUDIES SUGGEST that intrauterine growth-restricted infants are at increased risk of developing hypertension and other cardiovascular diseases in adult life (1). Fetal adaptations to an adverse intrauterine environment may include altered cellular differentiation and tissue growth to ensure short-term survival but may also lead to impaired cardiovascular and endocrine function later in adult life (1). Intrauterine growth restriction, in many cases, is thought to occur as a result of placental dysfunction leading to impaired oxygen and/or nutrient transfer to the fetus. Experimentally, undernutrition during pregnancy (2,6,10,18,28,32,40) or fetal exposure to elevated glucocorticoid levels (35, 36, 38) results in vascular dysfunction in adult offspring. However, the long-term effects of prenatal hypoxia are unclear.Exposure to chronic hypoxia in ovo results in reduced nitric oxide modulation of vascular responses in arteries from both e...

Sex differences in developmental programming models

“…Animal models Male-specific outcomes Langley-Evans et al (1996) Low-protein diet gives elevated blood pressure in male offspring relative to females Rat Kwong et al (2000) Low-protein diet increases blood pressure in male offspring Rat Ozaki et al (2001) Nutrient restriction (30% reduction) increases blood pressure and vascular dysfunction more in male offspring Rat Dodic et al (2002) Dexamethasone exposure gives increased blood pressure more in male offspring Sheep Franco Mdo et al (2002) Nutrient restriction (50%) reduces eNOS expression in aorta of male offspring Rat Alexander (2003) Reduced uterine perfusion causes sustained increase in blood pressure in male offspring Rat Ortiz et al (2003) Antenatal dexamethasone injection persistently elevates blood pressure in male offspring Rat Hemmings et al (2005) Hypoxia Lee & Rivier (1996) Ethanol exposure leads to exaggerated HPA stress response in young female offspring Rat Khan et al (2003) High-fat diet increases blood pressure in female offspring Rat Wilcoxon et al (2003) Ethanol exposure leads to decreased placental 11b-hydroxysteroid dehydrogenase-2 levels and left ventricular hypertrophy in female offspring High-fat diet leads to DNA hypomethylation in female placenta only Mouse Rodriguez et al (2011) Betamethasone exposure reduces associative learning more in female offspring Baboon Vickers et al (2011) Fructose exposure gives decreased placental weight, increased plasma leptin and glucose in female offspring Rat Epidemiology Male-specific outcomes Zaren et al (2000) Maternal smoking decreases birth weight and head circumference proportionally more in male offspring Human Goldenberg et al (2006) Placentas from preterm deliveries showed more lymphohistiocytic infiltration in male offspring Human Haley et al (2006) Prenatal exposure to alcohol increases the heart rate of female infant offspring more than males, but with the males showing a greater increase in plasma cortisol Human Mingrone et al (2008) Male offspring of obese mothers have higher levels of insulin secretion in response to GTT Human Female-specific outcomes Roseboom et al (2001) Higher rates of obesity in female offspring conceived during famine Human Clifton (2005) Maternal asthma in pregnancy causes altered placental glucocorticoid metabolism and growth in female offspring Human Stark et al (2009) Antenatal betamethasone administration increased placental 11b-hydroxysteroid dehydrogenase-2 activity in female offspring and this was positively correlated with mean arterial blood pressure…”

Sex differences in the fetal programming of hypertension

“…LBW in human is associated with vascular dysfunction (51), an observation supported by animal models of fetal programming (16,26,52,53). Thus, fetal programming contributes to both structural and physiological changes in the vasculature which may contribute to increased risk for development of CVD associated with LBW.…”

“…Different animal models include dietary undernutrition induced by global food restriction (9,10) or protein restriction during gestation (11,12,13,14,15), maternal hypoxia during gestation (16,17), placental insufficiency (18,19,20,21,22), or prenatal glucocorticoid treatment (23,24).…”

“…Moderate sodium intake leads to hypertension in male, but not female offspring; whereas high sodium intake during the same window of development programs male and female offspring (30). Hypoxia during gestation in the rat results in altered vascular function in male, but not female offspring (16). Thus, animal models of fetal programming indicate that male offspring are more sensitive to insults during development; and that female offspring are less sensitive, or protected against development of adult disease in response to fetal insult.…”

IUGR prevents IGF-1 upregulation in juvenile male mice by perturbing postnatal IGF-1 chromatin remodeling

“…The translational relevance of our D21 findings is that IUGR males are known to be at a disadvantage compared with IUGR females in many aspects of cardiovascular health especially in early adult life. Male offspring develop vascular dysfunction and hypertension, whereas female offspring seems to be protected (26,27). Literature over the past two decades has shown that IGF-1 not only controls growth properties but also has important effects on carbohydrate, lipid, and protein metabolism (2).…”