Fetal cerebrovascular acclimatization responses to high-altitude, long-term hypoxia: a model for prenatal programming of adult disease?

Longo, Lawrence D.; Pearce, William J.

doi:10.1152/ajpregu.00462.2004

Cited by 45 publications

(47 citation statements)

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“…Reduced nitric oxide modulation of vascular responses has also been found in fetal sheep exposed to chronic hypoxia at high altitude (33) and in embryonic and adult chickens after chronic exposure to hypoxia in ovo (42,43). Moreover, we recently demonstrated (55) decreased nitric oxide modulation of endothelium-dependent relaxation in 7-mo-old male offspring from dams exposed to hypoxia during pregnancy.…”

Section: Discussionmentioning

confidence: 54%

“…In mammals, the vascular effects of prenatal hypoxia have been examined primarily in the fetus (33,49) or the neonate (54). One recent study, however, demonstrated decreased vasoconstriction in the pulmonary vasculature of adult rat offspring after perinatal exposure to reduced oxygen, but these results are from a specialized vascular bed and the length of exposure to hypoxia included a 1-wk postnatal period (24).…”

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confidence: 99%

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

Hemmings¹,

Williams²,

Davidge³

2005

American Journal of Physiology-Heart and Circulatory Physiology

100

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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...

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Section: Discussionmentioning

confidence: 54%

mentioning

confidence: 99%

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

Hemmings¹,

Williams²,

Davidge³

2005

American Journal of Physiology-Heart and Circulatory Physiology

100

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“…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).…”

Section: Sex Differences In Fetal Programming: Animal Studiesmentioning

confidence: 99%

Sex differences in the fetal programming of hypertension

2008

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“…The ovine near-term fetus diverts an increased fraction of total cardiac output to the brain, when subjected to hypoxia during gestation. This implies that the cerebral vasculature is more dilated than the systemic vasculature (37,38). Increased vessel dilation was also the major factor contributing to increased CBF and maintenance of oxygenation in human volunteers taken to high altitude or subjected to acute hypoxia at sea level (66).…”

mentioning

confidence: 99%

Long-term hypoxia increases calcium affinity of BK channels in ovine fetal and adult cerebral artery smooth muscle

Xing

Lin

Thorington

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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Tao X, Lin MT, Thorington GU, Wilson SM, Longo LD, Hessinger DA. Long-term hypoxia increases calcium affinity of BK channels in ovine fetal and adult cerebral artery smooth muscle. Am J Physiol Heart Circ Physiol 308: H707-H722, 2015. First published January 16, 2015; doi:10.1152/ajpheart.00564.2014.-Acclimatization to high-altitude, long-term hypoxia (LTH) reportedly alters cerebral artery contraction-relaxation responses associated with changes in K ϩ channel activity. We hypothesized that to maintain oxygenation during LTH, basilar arteries (BA) in the ovine adult and near-term fetus would show increased large-conductance Ca 2ϩ activated potassium (BK) channel activity. We measured BK channel activity, expression, and cell surface distribution by use of patch-clamp electrophysiology, flow cytometry, and confocal microscopy, respectively, in myocytes from normoxic control and LTH adult and nearterm fetus BA. Electrophysiological data showed that BK channels in LTH myocytes exhibited 1) lowered Ca 2ϩ set points, 2) left-shifted activation voltages, and 3) longer dwell times. BK channels in LTH myocytes also appeared to be more dephosphorylated. These differences collectively make LTH BK channels more sensitive to activation. Studies using flow cytometry showed that the LTH fetus exhibited increased BK ␤1 subunit surface expression. In addition, in both fetal groups confocal microscopy revealed increased BK channel clustering and colocalization to myocyte lipid rafts. We conclude that increased BK channel activity in LTH BA occurred in association with increased channel affinity for Ca 2ϩ and left-shifted voltage activation. Increased cerebrovascular BK channel activity may be a mechanism by which LTH adult and near-term fetal sheep can acclimatize to long-term high altitude hypoxia. Our findings suggest that increasing BK channel activity in cerebral myocytes may be a therapeutic target to ameliorate the adverse effects of high altitude in adults or of intrauterine hypoxia in the fetus. ) channels, which are well known to modulate vascular tone and promote vasorelaxation (3,7,13,28).In contrast with the role of BK channels in mediating cerebrovascular response to short-term hypoxia, their role in acclimatization to long-term hypoxia (LTH) is less well known. During high-altitude LTH, the CBF in adult humans (23, 60) and sheep (34, 63) returns to normal following a period of transitional increased blood flow, as compiled by Brugniaux et al. (8). The ovine near-term fetus diverts an increased fraction of total cardiac output to the brain, when subjected to hypoxia during gestation. This implies that the cerebral vasculature is more dilated than the systemic vasculature (37, 38). Increased vessel dilation was also the major factor contributing to increased CBF and maintenance of oxygenation in human volunteers taken to high altitude or subjected to acute hypoxia at sea level (66). Because increased blood flow correlates directly with increased vessel diameter in mid-cerebral arteries in humans, as reviewed by Ains...

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Fetal cerebrovascular acclimatization responses to high-altitude, long-term hypoxia: a model for prenatal programming of adult disease?

Abstract: acclimatization responses to high-altitude, long-term hypoxia: a model for prenatal programming of adult disease? Am

Cited by 45 publications

References 58 publications

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

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

Sex differences in the fetal programming of hypertension

Long-term hypoxia increases calcium affinity of BK channels in ovine fetal and adult cerebral artery smooth muscle

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