Ghrelin attenuates preeclampsia-like features in rats by reprogramming decidual macrophages and improving placental remodeling

Preeclampsia (PE) is a severe, pregnancy-specific hypertensive disorder characterized by immune microenvironment dysregulation at the maternal-fetal interface. A key pathological feature is decidual macrophage phenotypic imbalance, where an excess of pro-inflammatory M1 macrophages contributes to placental dysfunction and systemic inflammation. Current treatments primarily manage symptoms, highlighting the need for therapies targeting underlying immune and placental defects. The Ghrelin/GHSR-1a axis is known for its immunomodulatory and anti-inflammatory effects, but its specific role in regulating decidual macrophage infiltration and phenotype in PE has remained unclear.

Researchers first analyzed Ghrelin/GHSR-1a axis expression in decidual tissues from 10 healthy pregnant women and 12 PE patients using immunohistochemistry (IHC). Subsequently, they established a lipopolysaccharide (LPS)-induced PE-like rat model to investigate the axis's functional role. Rats received exogenous Ghrelin supplementation, with a control arm receiving LPS alone. To confirm GHSR-1a dependence, another group received Ghrelin co-administered with D-lys-3-GHRP-6, a specific GHSR-1a antagonist. Primary endpoints included blood pressure, proteinuria, fetal growth, placental function, and maternal organ damage.

Clinical analysis revealed a severity-dependent compensatory escalation of the Ghrelin/GHSR-1a axis in PE decidual tissues, suggesting an endogenous protective response. In the LPS-induced PE-like rat model, exogenous Ghrelin supplementation significantly reversed PE-like phenotypes. This included attenuation of hypertension, proteinuria, and fetal growth restriction (FGR), alongside improved placental function and alleviated pathological damage to the maternal liver, kidney, and placenta. Mechanistically, Ghrelin modulated decidual macrophage phenotypic marker expression: it downregulated the M1 marker CD86 and upregulated the M2 marker CD163. Ghrelin also promoted trophoblast invasion and spiral artery remodeling by restoring laminin, α-cytokeratin 7 (α-CK7), and α-smooth muscle actin (α-SMA) expression in placental tissue.

All protective effects of Ghrelin were completely abrogated by co-administration of D-lys-3-GHRP-6, confirming the critical dependence on the Ghrelin/GHSR-1a axis.