Ghrelin promotes angiogenesis by activating the Jagged1/Notch2/VEGF pathway in preeclampsia

Abstract

Aim Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor (GHSR), has been found to be involved in the regulation of blood pressure; however, its effects in preeclampsia (PE) and the potential underlying mechanism remain poorly understood. In this study, we aimed to investigate the correlation between ghrelin and PE and reveal the possible mechanism underlying any relationship. Methods The levels of ghrelin and VEGF in the plasma of 6 early‐onset PE (EOPE), 6 late‐onset PE (LOPE) and 12 healthy pregnant (HP) women were detected using enzyme‐linked immunosorbent assay (ELISA). The recombinant plasmid, pCDH‐ghrelin, was designed to overexpress ghrelin in human umbilical vein endothelial cells (HUVECs). We analyzed angiogenesis in vitro and investigated the mechanism using MTT assay, colony formation assay, transwell migration assay, Matrigel‐induced tube formation assay and western blotting. Results Ghrelin was significantly decreased in EOPE patients (P < 0.05) but elevated in LOPE patients compared to HP groups (P > 0.05). There was a significant decrease in plasma level of VEGF in EOPE and LOPE patients compared to the controls (P < 0.05). The proliferation, migration and tube formation ability of HUVECs were enhanced after transfection with pCDH‐ghrelin. Ghrelin increased VEGF by activating the Jagged1/Notch2 pathway. Conclusion Our study uncovered that ghrelin has the potential to improve endothelial function by promoting angiogenesis through Jagged1/Notch2/VEGF pathway.

The Role of the Gastric Hormones Ghrelin and Nesfatin-1 in Reproduction

“…Interestingly, one study demonstrated that while in early onset preeclampsia (<34 weeks) ghrelin was reduced, it was increased in late onset preeclampsia [218]. Variations of ghrelin levels throughout pregnancy could be a reason while in contrast to the data displayed above there are also reports of increased circulating ghrelin levels in pregnancy-induced hypertension [213] and in mild and severe preeclampsia compared to healthy controls [216].…”

“…The extent of decrease of ghrelin in PCOS is supposedly depending on body weight and severity of PCOS [201,204], with an increase of ghrelin after treatment-induced normalization of hyperandrogenemia [201,205]. Secondly, observations that ghrelin was reduced in early onset preeclampsia, while it was increased in late onset preeclampsia [218], could explain why some studies report increased ghrelin in pregnancy-induced hypertension [213] and in mild and severe preeclampsia [216], while others describe reduced circulating ghrelin in preeclampsia [215,217]. Thirdly, a majority of studies in GDM observed decreased circulating ghrelin in patients compared to controls [64,65,88,219], with no difference 15 days after delivery in ghrelin serum between women with GDM and without diabetes [64], indicating a normalization with decreased disease activity.…”

“…Nevertheless, since ghrelin activated the Jagged1/Notch2 pathway inducing increased VEGF, which is decreased in preeclampsia [218] a positive effect of ghrelin on hypertension in pregnancy is assumed. This appears to be restricted to conditions in utero, since cord blood of newborns exposed to gestational hypertension was not different regarding ghrelin levels compared to cord blood of newborns that were not exposed [53].…”

Insights Into the Regulation of Offspring Growth by Maternally Derived Ghrelin

“…In preeclampsia, a known complication of pregnancy, ghrelin secretion is increased, and serum ghrelin levels have been reported to correlate negatively with blood pressure (55,56). It has been suggested that this is because ghrelin improves endothelial function by enhancing angiogenesis through the Jagged1/Notch2/VEGF pathway (57).…”

Estrogen and Preeclampsia: Potential of Estrogens as Therapeutic Agents in Preeclampsia

“… 27 Accordingly, various interventions to restore the angiogenic balance in preeclamptic pregnancies have been found to improve maternal and neonatal outcomes. 28 Using the first trimester of human placental villous explants, it has been shown that 2-methoxyestradiol may act by modulating vascular endothelial growth factor receptors (VEGFR-2). It was shown that exposure of placental villous explants to hypoxia produced preeclampsia-like features, including an increase in soluble fms-like tyrosine kinase-1 (antiangiogenic factor).…”