Critical Role for Macrophages in the Developmental Programming of Pancreatic β-Cell Area in Offspring of Hypertensive Pregnancies

Kate M. Root, Brian Akhaphong, Melissa A. Cedars, Alexa M. Molin, Margaretta E. Huchthausen, Connor F. Laule, Ronald R. Regal, Emilyn U. Alejandro, Jean F. Regal

Research output: Contribution to journalArticlepeer-review

Abstract

Preeclampsia is a pregnancy-specific complication with long-term negative outcomes for offspring, including increased susceptibility to type 2 diabetes (T2D) in adult-hood. In a rat reduced uteroplacental perfusion pressure (RUPP) model of chronic placental ischemia, maternal hypertension in conjunction with intrauterine growth restriction mimicked aspects of preeclampsia and resulted in female embryonic day 19 (e19) offspring with reduced β-cell area and increased β-cell apoptosis compared with offspring of sham pregnancies. Decreased pancreatic β-cell area persisted to postnatal day 13 (PD13) in females and could influence whether T2D developed in adulthood. Macrophage changes also occurred in islets in T2D. There-fore, we hypothesized that macrophages are crucial to reduction in pancreatic β-cell area in female offspring after chronic placental ischemia. Macrophage marker CD68 mRNA expression was significantly elevated in e19 and PD13 islets isolated from female RUPP offspring compared with sham. Postnatal injections of clodronate lipo-somes into female RUPP and sham offspring on PD2 and PD9 significantly depleted macrophages compared with injections of control liposomes. Depletion of macrophages rescued reduced β-cell area and increased β-cell proliferation and size in RUPP offspring. Our studies suggest that the presence of macrophages is important for reduced β-cell area in female RUPP offspring and changes in macrophages could contribute to development of T2D in adulthood.

Original languageEnglish (US)
Pages (from-to)2597-2611
Number of pages15
JournalDiabetes
Volume71
Issue number12
DOIs
StatePublished - Dec 2022

Bibliographical note

Funding Information:
Acknowledgments. The authors thank Dr. Cara Hegg, Whiteside Institute, University of Minnesota Duluth, for her advice and expertise in flow analysis and Dr. Ramkumar Mohan for technical support. Funding. This study was supported by Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, grant R21 HD100840. Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. K.M.R., M.A.C., M.E.H., and J.F.R. performed the animal studies, with collection of tissue samples, islets, and acinar. K.M.R., A.M.M., and C.F.L. developed flow cytometric methods for rat macrophages and conducted flow staining and analysis. K.M.R., R.R.R., and J.F.R. performed the primary analysis of the data. K.M.R., E.U.A., and J.F.R. designed the experiments and drafted the manuscript, which was reviewed, edited, and approved by all the authors. B.A. performed immunohistochemistry and insulin assays. M.A.C. performed the C-peptide assay. E.U.A. and J.F.R. are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Prior Presentation. Parts of this study were presented in abstract form at the Experimental Biology Meeting 2022, Philadelphia, PA, 2–5 April 2022.

Publisher Copyright:
© 2022 by the American Diabetes Association.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural

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