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Critical Role for Macrophages in the Developmental Programming of Pancreatic β-cell Area in Offspring of Gestational Hypertension

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posted on 2022-09-09, 17:46 authored by 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

Preeclampsia is a pregnancy-specific complication with long-term negative outcomes for offspring including increased susceptibility to type 2 diabetes (T2D) in adulthood. In rat Reduced Uteroplacental Perfusion Pressure (RUPP) model of chronic placental ischemia, maternal hypertension in conjunction with intrauterine growth restriction mimics aspects of preeclampsia and resulted in female embryonic day (e)19 offspring with reduced β-cell area and increased β-cell apoptosis compared to offspring of Sham pregnancies. Decreased pancreatic β-cell area persists to Postnatal Day (PD)13 in females and could influence whether T2D develops in adulthood. Macrophage changes also occur in islets in T2D. Therefore, we hypothesized that macrophages are crucial to reduction in pancreatic β-cell area in female offspring following chronic placental ischemia. The macrophage marker CD68 mRNA expression was significantly elevated in e19 and PD13 islets isolated from female RUPP offspring compared to Sham. Postnatal injections of clodronate liposomes into female RUPP and Sham offspring on PD2 and PD9 significantly depleted macrophages compared to animals injected with 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.

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NIH R21 HD100840

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