Abstract
During pregnancy, the uterine artery (UA) undergoes extensive remodeling to permit a 20–40 fold increase in blood flow with associated changes in the expression of a multitude of genes. This study used next-gen RNA sequencing technology to identify pathways and genes potentially involved in arterial adaptations in pregnant rat UA (gestation day 20) compared with non-pregnant rat UA (diestrus). A total of 2245 genes were differentially expressed, with 1257 up-regulated and 970 down-regulated in pregnant UA. Gene clustering analysis revealed a unique cluster of suppressed genes implicated in calcium signaling pathway and vascular smooth muscle contraction in pregnant UA. Transcription factor binding site motif scanning identified C2H2 ZF, AP-2 and CxxC as likely factors functional on the promoters of down-regulated genes involved in calcium signaling and vascular smooth muscle contraction. In addition, 1686 genes exhibited alternative splicing that were mainly implicated in microtubule organization and smooth muscle contraction. Cross-comparison analysis identified novel genes that were both differentially expressed and alternatively spliced; these were involved in leukocyte and B cell biology and lipid metabolism. In conclusion, this first comprehensive study provides a valuable resource for understanding the molecular mechanism underlying gestational uterine arterial adaptations during pregnancy.
Highlights
Pregnancy is one of the most complex reproductive activities of mammals, wherein extensive changes, especially in the uterine arteries (UA), occur to permit the supply of nutrients to the placenta and developing fetus
Studies have indicated that the differential expression of hormone receptor genes [15], calcium and potassium channels [16,17], growth factor genes (vascular endothelial growth factor [VEGF], placental growth factor, insulin-like growth factor 1 [IGF-I] and bone morphogenetic protein 6 [BMP6], vasodilator genes (nitric oxide, and hydrogen sulfide [cystathionine β-synthase]) [3,18] in uterine vasculature during pregnancy significantly impact vascular remodeling and vasodilation
These studies were conducted in isolation, and surprisingly, no studies have comprehensively examined global transcriptome and the associated pathways involved in normal gestational uterine vascular adaptations
Summary
Pregnancy is one of the most complex reproductive activities of mammals, wherein extensive changes, especially in the uterine arteries (UA), occur to permit the supply of nutrients to the placenta and developing fetus. In addition to the structural changes, uterine vascular reactivity is altered during pregnancy, with the general pattern reduced tone and enhanced vasodilation/blunted vasoconstriction [7] These differences between pregnancy and non-pregnancy are tightly regulated by the external environment, various endocrine factors, and the expression of a large number of genes [8,9,10]. Several other signaling pathways have been implicated in arterial remodeling, including matrix metalloproteinases (MMP) activation [19], adrenergic influences [20], toll-like receptors [21], cytoskeleton [22], including vimentin [23], and membrane-associated tyrosine kinases such as PYK2 [24] These studies were conducted in isolation, and surprisingly, no studies have comprehensively examined global transcriptome and the associated pathways involved in normal gestational uterine vascular adaptations
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