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 #
3R01HL079647-04S1
Application #
7619344
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Barouch, Winifred
Project Start
2005-02-01
Project End
2010-01-31
Budget Start
2008-03-11
Budget End
2010-01-31
Support Year
4
Fiscal Year
2008
Total Cost
$133,723
Indirect Cost
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
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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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