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Am J Perinatol 2018; 35(13): 1260-1270
DOI: 10.1055/s-0038-1642033
Original Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Antenatal Vitamin D Preserves Placental Vascular and Fetal Growth in Experimental Chorioamnionitis Due to Intra-amniotic Endotoxin Exposure

Michael W. Cookson
1   Section of Neonatology, The Pediatric Heart Lung Center, University of Colorado Anschutz Medical Center, Aurora, Colorado
,
Sharon L. Ryan
1   Section of Neonatology, The Pediatric Heart Lung Center, University of Colorado Anschutz Medical Center, Aurora, Colorado
2   Section of Neonatology, University of Colorado Anschutz Medical Center, Aurora, Colorado
,
Gregory J. Seedorf
1   Section of Neonatology, The Pediatric Heart Lung Center, University of Colorado Anschutz Medical Center, Aurora, Colorado
3   Section of Pulmonary Medicine, Department of Pediatrics, University of Colorado Anschutz Medical Center, Aurora, Colorado
,
R. Blair Dodson
1   Section of Neonatology, The Pediatric Heart Lung Center, University of Colorado Anschutz Medical Center, Aurora, Colorado
4   Department of United Therapeutics, Regenerative Medicine Lab, Durham, North Carolina
,
Steve H. Abman
1   Section of Neonatology, The Pediatric Heart Lung Center, University of Colorado Anschutz Medical Center, Aurora, Colorado
3   Section of Pulmonary Medicine, Department of Pediatrics, University of Colorado Anschutz Medical Center, Aurora, Colorado
,
Erica W. Mandell
1   Section of Neonatology, The Pediatric Heart Lung Center, University of Colorado Anschutz Medical Center, Aurora, Colorado
2   Section of Neonatology, University of Colorado Anschutz Medical Center, Aurora, Colorado
› Author Affiliations Funding This study was funded by Gilead Sciences Research Scholars Program, Section of Neonatology, University of Colorado.
Further Information

Publication History

22 January 2018

23 February 2018

Publication Date:
01 May 2018 (online)

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Abstract

Background Chorioamnionitis (CA) is associated with a high risk for the development of bronchopulmonary dysplasia (BPD) after preterm birth, but mechanisms that increase susceptibility for BPD and strategies to prevent BPD are uncertain. As a model of CA, antenatal intra-amniotic (IA) endotoxin (ETX) exposure alters placental structure, causes fetal growth restriction, increases perinatal mortality, and causes sustained cardiorespiratory abnormalities throughout infancy. Vitamin D (Vit D) has been shown to have both anti-inflammatory and proangiogenic properties. Antenatal IA treatment with Vit D (1,25-(OH)2D3) during IA ETX exposure improves survival and increases vascular and alveolar growth in infant rats. Whether IA ETX causes decreased placental vascular development and if the protective effects of prenatal Vit D treatment are due to direct effects on the fetus or to improved placental vascular development remain unknown.

Objective The objective of this study was to determine if IA ETX impairs placental vascular development and Vit D metabolism, and whether 1,25-(OH)2D3 treatment improves placental vascularity after IA ETX exposure during late gestation in pregnant rats.

Design/Methods Fetal rats were exposed to ETX (10 mg), ETX + 1,25-(OH)2D3 (1 ng/mL), 1,25-(OH)2D3 (1 ng/mL), or saline (control) via IA injection at E20 and delivered 2 days later. To assess placental vascular development, histologic sections from the placenta were stained for CD31 and vessel density per high power field (HPF) was determined and analyzed using Matlab software. To determine the effects of ETX on placental Vit D metabolism, Vit D receptor (VDR) and activity of the Vit D conversion enzyme, CYP27B1, were assayed from placental homogenates. Angiogenic mediators were measured by reverse transcription polymerase chain reaction by RNA extracted from placental tissue.

Results IA ETX reduced placenta and newborn birth weights by 22 and 20%, respectively, when compared with controls (placental weight: 0.60 vs. 0.47 g; p < 0.0001; birth weight: 4.68 vs. 5.88 g; p < 0.0001). IA 1,25-(OH)2D3 treatment increased birth weight by 12% in ETX-exposed pups (5.25 vs. 4.68 g; p < 0.001). IA ETX decreased placental vessel density by 24% in comparison with controls (1,114 vs. 848 vessels per HPF; p < 0.05). Treatment with IA 1,25-(OH)2D3 increased placenta vessel density twofold after ETX exposure (1,739 vs. 848); p < 0.0001), and increased vessel density compared with saline controls by 56% (1,739 vs. 1,114; p < 0.0001). IA ETX decreased both VDR and CYP27B1 expression by 83 and 35%, respectively (p < 0.01).

Conclusion IA ETX decreases placental growth and vessel density and decreases placental VDR and CYP27B1 protein expression, and that antenatal 1,25-(OH)2D3 restores placental weight and vessel density, as well as birth weight. We speculate that 1,25-(OH)2D3 treatment preserves placental function in experimental CA and that these effects may be mediated by increased vascular growth.

Keywords

vitamin D - endotoxin - placenta - chorioamnionitis - angiogenesis

Authors' Contributions

Conception and design: all authors. Drafting of article: E.W.M., S.R., M.W.C., and S.H.A. Analysis and data interpretation: E.W.M., M.W.C., and S.H.A.


 

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