Antenatal Maternal Long-Term Hypoxia: Acclimatization Responses with Altered Gene Expression in Ovine Fetal Carotid Arteries

Abstract

In humans and other species, long-term hypoxia (LTH) during pregnancy can lead to intrauterine growth restriction with reduced body/brain weight, dysregulation of cerebral blood flow (CBF), and other problems. To identify the signal transduction pathways and critical molecules, which may be involved in acclimatization to high altitude LTH, we conducted microarray with advanced bioinformatic analysis on carotid arteries (CA) from the normoxic near-term ovine fetus at sea-level and those acclimatized to high altitude for 110+ days during gestation. In response to LTH acclimatization, in fetal CA we identified mRNA from 38 genes upregulated >2 fold (P<0.05) and 9 genes downregulated >2-fold (P<0.05). The major genes with upregulated mRNA were SLC1A3, Insulin-like growth factor (IGF) binding protein 3, IGF type 2 receptor, transforming growth factor (TGF) Beta-3, and genes involved in the AKT and BCL2 signal transduction networks. Most genes with upregulated mRNA have a common motif for Pbx/Knotted homeobox in the promoter region, and Sox family binding sites in the 3′ un translated region (UTR). Genes with downregulated mRNA included those involved in the P53 pathway and 5-lipoxygenase activating proteins. The promoter region of all genes with downregulated mRNA, had a common 49 bp region with a binding site for DOT6 and TOD6, components of the RPD3 histone deacetylase complex RPD3C(L). We also identified miRNA complementary to a number of the altered genes. Thus, the present study identified molecules in the ovine fetus, which may play a role in the acclimatization response to high-altitude associated LTH.

Microarray gene expression analysis in ovine ductus arteriosus during fetal development and birth transition

“…In previous studies, we have described this technique in detail (23–25). Microarray analysis was conducted by utilizing the commercial services of GenUs BioSystems (Northbrook, IL).…”

Vitamin D status and metabolism in an ovine pregnancy model: effect of long-term, high-altitude hypoxia

“…for hypoxic fetal and placental weights, respectively). Recent reports have shown that LTH alters endocrine, vascular, and pulmonary physiology in the fetus (11,31,39). For this reason, we studied the effect of LTH on placental and fetal expression of vitamin D metabolic, transport, and receptor genes.…”

“…shown that normoxic and hypoxic pregnancies have similar outcomes but altered physiological adaptations (11,31,39). To assess the vitamin D status in this model, we analyzed the plasma levels of vitamin D metabolites [cholecalciferol, 25-OH-D, and 1␣,25-(OH) 2 D] in nonpregnant and pregnant ewes and their fetuses at normoxia (NMX; sea level) and long-term hypoxia (LTH; 3,800 m above sea level).…”

“…Our Center for Perinatal Biology has been investigating the maternal and fetal adaptations to high-altitude hypoxia, using a model in which the ewe is maintained at an altitude of 3,820 m from day 40 of gestation to near term (11,31,39). This model is characterized by decreases in both maternal and fetal arterial PO 2 that lead to cardiovascular, pulmonary, neuronal, endocrine, and other systems adaptations.…”

“…This model is characterized by decreases in both maternal and fetal arterial PO 2 that lead to cardiovascular, pulmonary, neuronal, endocrine, and other systems adaptations. This is a model of acclimatization where the fetus is not growth restricted but shows increased blood pressure, decreased cardiovascular output, and altered vascular and neuroendocrine responses to secondary stressors (11,31,39). Understanding the regulation of vitamin D status in this model would further our understanding on the adaptations of this species to high-altitude hypoxia.…”