Browsing by Autor "Vaughn A. Browne"

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Andean and Tibetan patterns of adaptation to high altitude
(Wiley, 2013) Abigail W. Bigham; Megan J. Wilson; Colleen G. Julian; Melisa Kiyamu; Enrique Vargas; Fabiola Lèon‐Velarde; Maria C. Rivera; Carmelo Rodriquez; Vaughn A. Browne; Esteban J. Parra
These results contribute to our understanding of the unique set of adaptations developed in different highland groups to the hypoxia of high altitude. Overall, the results provide key insights into the patterns of genetic adaptation to high altitude in Andean and Tibetan populations.
Do Anti-angiogenic or Angiogenic Factors Contribute to the Protection of Birth Weight at High Altitude Afforded by Andean Ancestry?
(Springer Nature, 2010) R. Daniela Dávila; Colleen G. Julian; Megan J. Wilson; Vaughn A. Browne; Carmelo Rodriguez; Abigail W. Bigham; Mark D. Shriver; Enrique Vargas; Lorna G. Moore
Do Cytokines Contribute to the Andean-Associated Protection From Reduced Fetal Growth at High Altitude?
(Springer Nature, 2010) R. Daniela Dávila; Colleen G. Julian; Megan J. Wilson; Vaughn A. Browne; Carmelo Rodriguez; Abigail W. Bigham; Mark D. Shriver; Enrique Vargas; Lorna G. Moore
Erythropoietin and Soluble Erythropoietin Receptor: A Role for Maternal Vascular Adaptation to High-Altitude Pregnancy
(Oxford University Press, 2016) Gabriel H. Wolfson; Enrique Vargas; Vaughn A. Browne; Lorna G. Moore; Colleen G. Julian
Our findings suggest that an augmented pregnancy-associated rise in Epo may be important for successful vascular adaptation to pregnancy at HA. We further speculate that the elevated sEpoR observed in PreE vs controls at HA impedes the effect of Epo to maintain endothelial function and may, in turn, be of pathological relevance for PreE at HA.
High-end arteriolar resistance limits uterine artery blood flow and restricts fetal growth in preeclampsia and gestational hypertension at high altitude
(American Physiological Society, 2011) Vaughn A. Browne; Lilian Toledo‐Jaldin; R. Daniela Dávila; Luis P. Lopez; Henry Yamashiro; Darleen Cioffi‐Ragan; Colleen G. Julian; Megan J. Wilson; Abigail W. Bigham; Mark D. Shriver
The reduction in infant birth weight and increased frequency of preeclampsia (PE) in high-altitude residents have been attributed to greater placental hypoxia, smaller uterine artery (UA) diameter, and lower UA blood flow (Q(UA)). This cross-sectional case-control study determined UA, common iliac (CI), and external iliac (EI) arterial blood flow in Andeans residing at 3,600-4,100 m, who were either nonpregnant (NP, n = 23), or experiencing normotensive pregnancies (NORM; n = 155), preeclampsia (PE, n = 20), or gestational hypertension (GH, n = 12). Pregnancy enlarged UA diameter to ~0.62 cm in all groups, but indices of end-arteriolar vascular resistance were higher in PE or GH than in NORM. Q(UA) was lower in early-onset (≤34 wk) PE or GH than in NORM, but was normal in late-onset (>34 wk) illness. Left Q(UA) was consistently greater than right in NORM, but the pattern reversed in PE. Although Q(CI) and Q(EI) were higher in PE and GH than NORM, the fraction of Q(CI) distributed to the UA was reduced 2- to 3-fold. Women with early-onset PE delivered preterm, and 43% had stillborn small for gestational age (SGA) babies. Those with GH and late-onset PE delivered at term but had higher frequencies of SGA babies (GH=50%, PE=46% vs. NORM=15%, both P < 0.01). Birth weight was strongly associated with reduced Q(UA) (R(2) = 0.80, P < 0.01), as were disease severity and adverse fetal outcomes. We concluded that high end-arteriolar resistance, not smaller UA diameter, limited Q(UA) and restricted fetal growth in PE and GH. These are, to our knowledge, the first quantitative measurements of Q(UA) and pelvic blood flow in early- vs. late-onset PE in high-altitude residents.
Inhibition of peroxisome proliferator‐activated receptor γ: a potential link between chronic maternal hypoxia and impaired fetal growth
(Wiley, 2013) Colleen G. Julian; Ivana V. Yang; Vaughn A. Browne; Enrique Vargas; Carmelo Rodriguez; Brent S. Pedersen; Lorna G. Moore; David A. Schwartz
Chronic exposure to hypoxia raises the risk of pregnancy disorders characterized by maternal vascular dysfunction and diminished fetal growth. In an effort to identify novel pathways for these hypoxia-related effects, we assessed gene expression profiles of peripheral blood mononuclear cells (PBMCs) obtained from 43 female, high-altitude or sea-level residents in the nonpregnant state or during pregnancy (20 or 36 wk). Hypoxia-related fetal growth restriction becomes apparent between 25 and 29 wk of gestation and continues until delivery. Our sampling strategy was designed to capture changes occurring before (20 wk) and during (36 wk) the time frame of slowed fetal growth. PBMC gene expression profiles were generated using human gene expression microarrays and compared between altitudes. Biological pathways were identified using pathway analysis. Modest transcriptional differences were observed between altitudes in the nonpregnant state. Of the genes that were differentially expressed at high altitude vs. sea level during pregnancy (20 wk: 59 probes mapped to 41 genes; 36 wk: 985 probes mapped to 700 genes), several are of pathological relevance for fetal growth restriction. In particular, transcriptional changes were consistent with the negative regulation of peroxisome proliferator-activated receptor γ (PPARγ) at high altitude; such effects were accompanied by reduced birth weight (P <0.05) and head circumference (P <0.01) at high altitude vs. sea level. Our findings indicate that chronic exposure to hypoxia during pregnancy alters maternal gene expression patterns in general and, in particular, expression of key genes involved in metabolic homeostasis that have been proposed to play a role in the pathophysiology of fetal growth restriction.
MaternalPRKAA1andEDNRAgenotypes are associated with birth weight, andPRKAA1with uterine artery diameter and metabolic homeostasis at high altitude
(American Physical Society, 2014) Abigail W. Bigham; Colleen G. Julian; Megan J. Wilson; Enrique Vargas; Vaughn A. Browne; Mark D. Shriver; Lorna G. Moore
Low birth weight and intrauterine growth restriction (IUGR) increase the risk of mortality and morbidity during the perinatal period as well as in adulthood. Environmental and genetic factors contribute to IUGR, but the influence of maternal genetic variation on birth weight is largely unknown. We implemented a gene-by-environment study wherein we utilized the growth restrictive effects of high altitude. Multigenerational high-altitude residents (Andeans) are protected from altitude-associated IUGR compared with recent migrants (Europeans). Using a combined cohort of low- and high-altitude European and Andean women, we tested 63 single nucleotide polymorphisms (SNPs) from 16 natural selection-nominated candidate gene regions for associations with infant birth weight. We identified significant SNP associations with birth weight near coding regions for two genes involved in oxygen sensing and vascular control, PRKAA1 and EDNRA, respectively. Next, we identified a significant association for the PRKAA1 SNP with an intermediate phenotype, uterine artery diameter, which has been shown to be related to Andean protection from altitude-associated reductions in fetal growth. To explore potential functional relationships for the effect of maternal SNP genotype on birth weight, we evaluated the relationship between maternal PRKAA1 SNP genotype and gene expression patterns in general and, in particular, of key pathways involved in metabolic homeostasis that have been proposed to play a role in the pathophysiology of IUGR. Our observations suggest that maternal genetic variation within genes that regulate oxygen sensing, metabolic homeostasis, and vascular control influence fetal growth and birth weight outcomes and hence Andean adaptation to high altitude.
PlGF is greater and sFLT‐1 lower in multigenerational vs. shorter‐term pregnant residents of high altitude
(Wiley, 2008) R. Daniela Dávila; Colleen G. Julian; Vaughn A. Browne; Megan J. Wilson; Jennifer L. Hageman; Henry Yamashiro; Armando Rodríguez; Carmelo Rodriguez; Enrique Vargas; Lorna G. Moore
INTRODUCTION. An imbalance between angiogenic and anti‐angiogenic factors likely plays an etiological role in fetal growth restriction. Since multigenerational high‐altitude (HA) Andean (AND) vs. shorter‐term, European (EUR) ancestry protects against fetal growth restriction at HA, we hypothesized that the angiogenic factor PlGF was elevated and the anti‐angiogenic factor sFlt‐1 reduced. MATERIALS AND METHODS. Pregnant women residing at low (400 m; AND n=36, EUR n=39) or high (3600m; AND n=46, EUR n=33) altitude in Bolivia were studied at 20 and 36 wk of pregnancy and 4 mo postpartum. Plasma sFlt1 and PlGF levels were determined by ELISA and data analyzed by ANOVA. RESULTS. Pregnancy increased PlGF and sFlt‐1 in EUR and AND women (p<0.001). PlGF increased in AND women at HA in early pregnancy and declined at 36 wk compared EUR values (interaction between pregnancy, altitude and ancestry, p<0.05). At HA, sFlt‐1 was greater in EUR than AND women at 20 and 36 wk (p<0.001). The sFlt‐1/PlGF ratio rose from 20 wk to 36 wk in EUR women at both altitudes and in HA AND women but not in the LA AND, and tended to be lower in AND vs. EUR women near term (p<0.10). CONCLUSIONS. Lower sFLT‐1 and higher PlGF levels may help protect multigenerational AND compared with shorter‐term EUR HA‐residents from fetal growth restriction. (NIH HL079647 and HL 14985)
Potential role for elevated maternal enzymatic antioxidant status in Andean protection against altitude-associated SGA
(Informa, 2011) Colleen G. Julian; Enrique Vargas; Vaughn A. Browne; Megan J. Wilson; Abigail W. Bigham; Carmelo Rodriguez; Joe M. McCord; Lorna G. Moore
Oxidative stress has been implicated in the uteroplacental ischemia characteristic of preeclampsia and small-for-gestational-age (SGA) birth, both of which are more common at high (>2500 m) vs low altitude. Since Andeans are protected relative to Europeans from the altitude-associated rise in SGA, we asked whether alterations in maternal antioxidant status or oxidative stress contributed to their protection. Enzymatic antioxidant (erythrocyte catalase and superoxide dismutase [SOD]) activity and a plasma marker of lipid peroxidation (8-iso-PGF2α) were measured during pregnancy and in the non-pregnant state in Andean or European residents of low (400 m) or high altitude (3600-4100 m). Pregnancy and altitude increased catalase and/or SOD activity to a greater extent in Andeans than Europeans. 8-iso-PGF2α levels were independent of altitude and pregnancy. SOD was lower in mothers of SGA infants at weeks 20 and 36. Our findings are consistent with the possibility that elevated enzymatic antioxidant activity contributes to Andean protection against altitude-associated SGA.
Role of cytokines in altitude-associated preeclampsia
(Elsevier BV, 2011) R. Daniela Dávila; Colleen G. Julian; Vaughn A. Browne; Lillian Toledo-Jaldin; Megan J. Wilson; Armando Rodríguez; Enrique Vargas; Lorna G. Moore
The role of antioxidant & oxidative status in the protection against altitude‐associated reductions in uterine artery (UA) blood flow & fetal growth afforded by Andean ancestry
(Wiley, 2008) Colleen G. Julian; Enrique Vargas; Joe M. McCord; Jennifer L. Hageman; R. Daniela Dávila; Henry Yamashiro; Megan J. Wilson; Carmelo Rodriguez; Armando Rodríguez; Vaughn A. Browne
Objective: To determine the role of antioxidant & oxidative status in the protection of uterine artery blood flow (UAVF) & fetal growth at high altitude in Andean populations. Methods: Erythrocyte catalase (CAT) & superoxide dismutase (SOD), plasma isoprostanes (8‐ISO‐PGF‐2α) & UA VF were measured at 20 & 36w of pregnancy & and in the non‐pregnant state in Andean (AND) & European (EUR) women at low (LA, 416m) or high (HA, 3600m) altitude. CAT, SOD & 8‐iso‐PGF‐2α were assessed by spectrometry, UA VF by Doppler ultrasound & birth weight (BW) by medical records review. Data was analyzed by t‐tests, 1‐ & 2‐way ANOVA. Results: At LA, ancestry had no effect on CAT or SOD. AND had higher CAT (20 & 36w p<0.05) & SOD activity (36w p<0.05) than EUR at HA. At HA, UA diameter and UA VF were greater in AND than EUR. Altitude decreased BW in AND (p<0.05) and EUR (p<0.01), and at HA EUR ancestry reduced BW (β= − 0.238 p<0.05). Small‐for‐gestational age (SGA) infants occurred 2‐times more frequently at HA than LA in EUR. SOD was lower at 20w in SGA at both altitues, or HA alone (all p<0.05). In EUR, CAT tended to be lower at 20w in SGA. 8‐ISO‐PGF2α reduced UA diam (p<0.05) & UA VF (p<0.01) in all women. Conclusion: Elevated endogenous antioxidant activity may contribute to the protection against altitude‐associated reductions in UA blood flow & fetal growth afforded by Andean ancestry. NIH HL079647 ,AHA 0610129Z & NSF BCS‐064719.
Uterine artery blood flow, fetal hypoxia and fetal growth
(Royal Society, 2015) Vaughn A. Browne; Colleen G. Julian; Lillian Toledo-Jaldin; Darleen Cioffi‐Ragan; Enrique Vargas; Lorna G. Moore
Evolutionary trade-offs required for bipedalism and brain expansion influence the pregnancy rise in uterine artery (UtA) blood flow and, in turn, reproductive success. We consider the importance of UtA blood flow by reviewing its determinants and presenting data from 191 normotensive (normal, n = 125) or hypertensive (preeclampsia (PE) or gestational hypertension (GH), n = 29) Andean residents of very high (4100-4300 m) or low altitude (400 m, n = 37). Prior studies show that UtA blood flow is reduced in pregnancies with intrauterine growth restriction (IUGR) but whether the IUGR is due to resultant fetal hypoxia is unclear. We found higher UtA blood flow and Doppler indices of fetal hypoxia in normotensive women at high versus low altitude but similar fetal growth. UtA blood flow was markedly lower in early-onset PE versus normal high-altitude women, and their fetuses more hypoxic as indicated by lower fetal heart rate, Doppler indices and greater IUGR. We concluded that, despite greater fetal hypoxia, fetal growth was well defended by higher UtA blood flows in normal Andeans at high altitude but when compounded by lower UtA blood flow in early-onset PE, exaggerated fetal hypoxia caused the fetus to respond by decreasing cardiac output and redistributing blood flow to help maintain brain development at the expense of growth elsewhere. We speculate that UtA blood flow is not only an important supply line but also a trigger for stimulating the metabolic and other processes regulating feto-placental metabolism and growth. Studies using the natural laboratory of high altitude are valuable for identifying the physiological and genetic mechanisms involved in human reproductive success.