Ward, E. J. et al. (2023) Placental inflammation leads to abnormal embryonic heart development. Circulation, 147(12), pp. 956-972. (doi: 10.1161/CIRCULATIONAHA.122.061934) (PMID:36484244) (PMCID:PMC10022676)
![[img]](https://eprints.gla.ac.uk/style/images/fileicons/text.png) |
Text
288066.pdf - Published Version Available under License Creative Commons Attribution. 7MB |
Abstract
Background: Placental heart development and embryonic heart development occur in parallel, and these organs have been proposed to exert reciprocal regulation during gestation. Poor placentation has been associated with congenital heart disease, an important cause of infant mortality. However, the mechanisms by which altered placental development can lead to congenital heart disease remain unresolved. Methods: In this study, we use an in vivo neutrophil-driven placental inflammation model through antibody depletion of maternal circulating neutrophils at key stages during time-mated murine pregnancy: embryonic days 4.5 and 7.5. Pregnant mice were culled at embryonic day 14.5 to assess placental and embryonic heart development. A combination of flow cytometry, histology, and bulk RNA sequencing was used to assess placental immune cell composition and tissue architecture. We also used flow cytometry and single-cell sequencing to assess embryonic cardiac immune cells at embryonic day 14.5 and histology and gene analyses to investigate embryonic heart structure and development. In some cases, offspring were culled at postnatal days 5 and 28 to assess any postnatal cardiac changes in immune cells, structure, and cardiac function, as measured by echocardiography. Results: In the present study, we show that neutrophil-driven placental inflammation leads to inadequate placental development and loss of barrier function. Consequently, placental inflammatory monocytes of maternal origin become capable of migration to the embryonic heart and alter the normal composition of resident cardiac macrophages and cardiac tissue structure. This cardiac impairment continues into postnatal life, hindering normal tissue architecture and function. Last, we show that tempering placental inflammation can prevent this fetal cardiac defect and is sufficient to promote normal cardiac function in postnatal life. Conclusions: Taken together, these observations provide a mechanistic paradigm whereby neutrophil-driven inflammation in pregnancy can preclude normal embryonic heart development as a direct consequence of poor placental development, which has major implications on cardiac function into adult life.
| Item Type: | Articles |
|---|---|
| Additional Information: | This work was funded by a British Heart Foundation intermediate basic science research fellowship (SN; FS/17/1/32528). This work is aligned with the British Heart Foundation Accelerator Award (AA/18/5/34222) to Queen Mary, which focuses on cardiac inflammation; Wellcome Trust Investigator Award Wellcome Trust investigator award (GJG;217093/Z/19/Z; GJG); and MRC programme grant (GJG; MRV0109721). The flow cytometry core facility was funded by CRUK (core award C16420/A18066). |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Graham, Professor Gerard |
| Authors: | Ward, E. J., Bert, S., Fanti, S., Malone, K. M., Maughan, R. T., Gkantsinikoudi, C., Prin, F., Volpato, L. K., Piovezan, A. P., Graham, G. J., Dufton, N. P., Perretti, M., Marelli-Berg, F. M., and Nadkarni, S. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Infection & Immunity |
| Research Centre: | College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Immunobiology |
| Journal Name: | Circulation |
| Publisher: | American Heart Association |
| ISSN: | 0009-7322 |
| ISSN (Online): | 1524-4539 |
| Published Online: | 09 December 2022 |
| Copyright Holders: | Copyright © 2023 The Authors |
| First Published: | First published in Circulation 147(12): 956-972 |
| Publisher Policy: | Reproduced under a Creative Commons License |
University Staff: Request a correction | Enlighten Editors: Update this record
Funder and Project Information
Funder and Project Information