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Angiogenic and Inflammatory microRNA Regulation in a Mouse Model of Fetal Growth Restriction
Lauren T Gallagher1, Clyde J Wright2, Tanner Lehmann1
1Laboratory for Fetal and Regenerative Biology, Department of Surgery, University of Colorado Denver School of Medicine, Aurora, Colorado; Division of Pediatric Surgery, Children's Hospital Colorado, Aurora, Colorado.
Introduction:
Fetal growth restriction (FGR) is associated with impaired angiogenesis and chronic inflammation. MicroRNAs (miRs) are short noncoding RNAs that regulate gene expression at the post-transcriptional level by targeting messenger RNA (mRNA) for degradation or by suppressing translation. We hypothesize that dysregulation of miR-15b, an antiangiogenic miR, and miR-146a, an anti-inflammatory miR, are associated with the FGR's pathogenesis.
Methods:
Pregnant mice were provided ad libitum access to food between E1 and E8. From E9-E18, dams received either a 50% caloric restricted diet (FGR) or continued ad libitum access (controls). Placentas were harvested at E18.5 and total RNA was extracted. Gene expression levels of miRs and mRNAs were compared between FGR and control placentas.
Results:
Placentas affected by FGR demonstrated increased expression of miR-15b. Vascular endothelial growth factor alpha, which is downregulated in response to increased levels of miR-15b, was suppressed. The anti-inflammatory miR, miR-146a, was downregulated, resulting in upregulation of proinflammatory (IL-6, IL-8, and NFkB1) and oxidative stress (HIF-1α, SOD2, and Nox2) mediators.
Conclusions:
Aberrant angiogenesis and chronic inflammation seen in FGR appear to be associated with dysregulated miR-15b and miR-146a gene expression, respectively. This observation suggests these miRs play a post-transcriptional regulatory role in FGR, providing an insight into possible therapeutic targets.
Insights
Dysregulated microRNAs (miRs) miR-15b and miR-146a are linked to fetal growth restriction (FGR). Upregulated miR-15b impairs blood vessel formation, while downregulated miR-146a promotes inflammation in FGR placentas.
Area of Science:
- Reproductive biology
- Molecular genetics
- Developmental biology
Background:
- Fetal growth restriction (FGR) is characterized by impaired angiogenesis and chronic inflammation.
- MicroRNAs (miRs) are key regulators of gene expression, influencing various biological processes.
- Dysregulation of specific miRs may contribute to FGR pathogenesis.
Purpose of the Study:
- To investigate the role of miR-15b and miR-146a in the pathogenesis of FGR.
- To determine if altered expression of these miRs is associated with impaired angiogenesis and inflammation in FGR.
Main Methods:
- A mouse model of FGR was established using caloric restriction during pregnancy.
- Placental tissues were collected from FGR and control groups.
- Quantitative real-time PCR was used to compare miR and mRNA expression levels between groups.
Main Results:
- FGR placentas showed increased expression of miR-15b, correlating with suppressed vascular endothelial growth factor alpha.
- miR-146a was downregulated in FGR placentas, leading to increased levels of pro-inflammatory mediators (IL-6, IL-8, NFkB1) and oxidative stress markers (HIF-1α, SOD2, Nox2).
Conclusions:
- Aberrant angiogenesis and chronic inflammation in FGR are associated with dysregulated miR-15b and miR-146a expression.
- These findings suggest a post-transcriptional regulatory role for miR-15b and miR-146a in FGR.
- The study highlights these miRs as potential therapeutic targets for FGR.
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