Reduced 02 availability at high altitude restricts fetal growth and increases the frequency of preeclampsia, making high-altitude residents the single largest group at risk for these complications. We have shown that this altitude-related increase is due, in part, to alterations in maternal vascular reactivity; growth and remodeling that lessen uterine artery (UA) blood flow. Moreover our data demonstrate that multigenerational compared with shorter-term high-altitude residents are protected from the altitude-associated increase in IUGR due to greater UA blood flow. Based on recent evidence demonstrating that hypoxia-inducible transcription factors (HIFs) play a central role in regulating O2-sensitive genes, are implicated in pregnancy disorders, and our preliminary data that they are differentially regulated in long- vs. short-term populations, we propose to test the overall hypothesis that genetic variants in HIF-targeted or regulatory pathways protect multigenerational high-altitude residents from hypoxia-associated IUGR. Serial studies are proposed during pregnancy and again postpartum in 100 high- (3600 m) and 100 low- (300 m) altitude residents. Women will be drawn evenly from populations with multigenerational (Andean) vs. shorter-term (European) residence at high altitude.
Specific aims are to test whether 1) Andean vs. European ancestry is protective against hypoxia-induced IUGR due genetic factors influencing HIF-targeted secretory gene products and UA blood flow, 2) differences in UA blood flow and fetal growth are due to HIF-targeted and -regulatory genes, and 3) Andean-European differences in maternal physiologic responses to pregnancy and fetal growth are the result of actions of HIF-targeted or regulatory genes influencing UA vasoconstriction, vasodilation, or growth.
These aims are supported by preliminary data demonstrating protection from hypoxia-associated IUGR in Andean vs. European high-altitude residents together with greater UA blood flow, lower endothelin-1 levels (EDN1) and the presence of distinctive genetic variants in or near the EDN1 as well as other, HIF-targeted genes. Thus we have designed a novel strategy for coupling genomic approaches with more traditional physiological tools to identify genes influencing maternal vascular response to pregnancy and hypoxia-induced IUGR. The proposed studies are relevant not only for the 140 million high-altitude residents worldwide, including more than 100,000 in Colorado, but also the larger number of women whose pregnancies are complicated by uteroplacental ischemia and/or fetal hypoxia.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL079647-05
Application #
7799394
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Barouch, Winifred
Project Start
2005-02-01
Project End
2012-07-31
Budget Start
2009-06-01
Budget End
2012-07-31
Support Year
5
Fiscal Year
2008
Total Cost
$98,971
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
Wolfson, Gabriel H; Vargas, Enrique; Browne, Vaughn A et al. (2017) Erythropoietin and Soluble Erythropoietin Receptor: A Role for Maternal Vascular Adaptation to High-Altitude Pregnancy. J Clin Endocrinol Metab 102:242-250
Moore, Lorna G (2017) Human Genetic Adaptation to High Altitudes: Current Status and Future Prospects. Quat Int 461:4-13
Julian, Colleen G; Pedersen, Brent S; Salmon, Carlos Salinas et al. (2015) Unique DNA Methylation Patterns in Offspring of Hypertensive Pregnancy. Clin Transl Sci 8:740-5
Pomeroy, Emma; Wells, Jonathan C K; Stanojevic, Sanja et al. (2015) Surname-inferred Andean ancestry is associated with child stature and limb lengths at high altitude in Peru, but not at sea level. Am J Hum Biol 27:798-806
Julian, Colleen Glyde; Gonzales, Marcelino; Rodriguez, Armando et al. (2015) Perinatal hypoxia increases susceptibility to high-altitude polycythemia and attendant pulmonary vascular dysfunction. Am J Physiol Heart Circ Physiol 309:H565-73
Osol, George; Moore, Lorna G (2014) Maternal uterine vascular remodeling during pregnancy. Microcirculation 21:38-47
Julian, Colleen G; Yang, Ivana V; Browne, Vaughn A et al. (2014) Inhibition of peroxisome proliferator-activated receptor ?: a potential link between chronic maternal hypoxia and impaired fetal growth. FASEB J 28:1268-79
Julian, Colleen Glyde; Vargas, Enrique; Gonzales, Marcelino et al. (2013) Sleep-disordered breathing and oxidative stress in preclinical chronic mountain sickness (excessive erythrocytosis). Respir Physiol Neurobiol 186:188-96
Eckman, Delrae M; Gupta, Ridhima; Rosenfeld, Charles R et al. (2012) Pregnancy increases myometrial artery myogenic tone via NOS- or COX-independent mechanisms. Am J Physiol Regul Integr Comp Physiol 303:R368-75
Galanter, Joshua Mark; Fernandez-Lopez, Juan Carlos; Gignoux, Christopher R et al. (2012) Development of a panel of genome-wide ancestry informative markers to study admixture throughout the Americas. PLoS Genet 8:e1002554

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