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Developmental Maturation and Alpha-1 Adrenergic Receptors-Mediated Gene Expression Changes in Ovine Middle Cerebral Arteries

ABSTRACT: The Alpha Adrenergic Signaling Pathway is one of the chief regulators of cerebrovascular tone and cerebral blood flow (CBF), mediating its effects in the arteries through alpha1-adrenergic receptors (Alpha1AR). In the ovine middle cerebral artery (MCA), with development from a fetus to an adult, others and we have shown that Alpha1AR play a key role in contractile responses, vascular development, remodeling, and angiogenesis. Importantly, Alpha1AR play a significant role in CBF autoregulation, which is incompletely developed in a premature fetus as compared to a near-term fetus. However, the mechanistic pathways are not completely known. Thus, we tested the hypothesis that as a function of maturation and in response to Alpha1AR stimulation there is a differential gene expression in the ovine MCA. We conducted microarray analysis on transcripts from MCAs of premature fetuses (96-day), near-term fetuses (145-day), newborn lambs, and non-pregnant adult sheep (2-year) following stimulation of Alpha1AR with phenylephrine (a specific agonist). We observed several genes which belonged to pro-inflammatory and vascular development/angiogenesis pathway significantly altered in all of the four age groups. We also observed age-specific changes in gene expression–mediated by Alpha1AR stimulation in the different developmental age groups. These findings imply complex regulatory mechanisms of cerebrovascular development.

ORGANISM(S): Ovis aries

PROVIDER: GSE109325 | GEO | 2018/01/18

SECONDARY ACCESSION(S): PRJNA430434

REPOSITORIES: GEO

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Project description:In humans and other species, Longlong-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 in humans and rodents. In contrast, sheep appear to undergo relatively successful acclimatization, not demonstrating any of the above-mentioned problems except at extremely high altitude. To identify the signal transduction genetic pathways and those 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 fFold; (P < 0.05) and 9 genes downregulated (> 2-f 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. The majority of genes with upregulated mRNA have a common motif for Pbx/Knotted homeobox in the promoter region, and Sox family binding sites in the 3M-bM-^@M-^Y 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 help it to play a role in the acclimatizatione successfully response to high-altitude associated LTH. In these series of experiments we examined changes in gene expression in sheep carotids. Pregnant sheep and non-pregnant adult sheep were exposed to 110 days of hypoxia at 3801 meters of altitude. Carotid arteries from fetuses from non-pregnant adult from sea-level controls and those from high-altitude were compared by Agilent ovine custom array

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Developmental Maturation and Alpha-1 Adrenergic Receptors-Mediated Gene Expression Changes in Ovine Middle Cerebral Arteries

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