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.
Highlights
The cellular and molecular mechanisms by which an organism acclimatizes to high altitude long-term hypoxia (LTH) are complex and not well understood
As a consequence of antenatal maternal long-term hypoxia, we did not observe a significant reduction in the fetal body or brain
We identified a number of key genes, cis-regulatory elements, and miRNA that may play an important role in successful acclimatization of the ovine fetal cranial vasculature in association with exposure to in-utero long-term hypoxia (110 days)
Summary
The cellular and molecular mechanisms by which an organism acclimatizes to high altitude long-term hypoxia (LTH) are complex and not well understood. The sheep fetus undergoes successful acclimatization without the LTH-induced pathological conditions observed in many other species [3,4]. This has been reported in the sheep by others [5]. High-altitude (2,740 to 3,100 m) exposed human infants have been reported to demonstrate intrauterine growth restriction, reduced weight of brain and other organs, increased incidence of pulmonary hypertension, as well as other pathological conditions [6,7]. Despite the higher elevation in our study (3,801 m), the influence of hypoxic stress on the sheep fetus is attenuated, representing a unique adaptive characteristic
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