Chemerin as a Novel Mediator of Fetal Endothelial Dysfunction in Gestational Diabetes Mellitus: Integration of Bioinformatics, Clinical, and In Vitro Evidence.

OBJECTIVE

This study aimed to elucidate chemerin's role in gestational diabetes mellitus (GDM)-related fetal endothelial dysfunction and its association with non-invasive hemodynamic parameters.

METHODS

We integrated bioinformatics (GSE87295 dataset, n = 5/group), a prospective clinical cohort (30 GDM, 31 controls), and functional in vitro experiments. Chemerin and von Willebrand factor (vWF) were quantified by ELISA. Fetal aortic pulse wave velocity (APV) was assessed by Doppler ultrasound. Human umbilical vein endothelial cells (HUVECs) were treated with recombinant chemerin (0-40 nM).

RESULTS

Transcriptomic analysis revealed chemerin (RARRES2) co-expression with inflammatory and metabolic genes, with tissue-level mRNA downregulation but pathway activation in GDM. Clinically, GDM exhibited elevated umbilical cord serum chemerin (median [IQR]: 244980.49 [244890.56-245318.24] vs. 244463.32 [244429.48-244589.77] pg/mL, p < 0.0001) and vWF (17727.80 [8267.68-40286.38] vs. 11804.38 [2793.55-30280.01] ng/mL, p < 0.0001), alongside reduced fetal APV (28.4 ± 3.1 vs. 35.2 ± 2.8 cm/s, p < 0.0001). Serum chemerin correlated positively with vWF (r = 0.538, p < 0.0001) and negatively with APV (r = -0.493, p < 0.0001). In vitro, chemerin induced dose-dependent impairment of HUVEC migration (40% reduction at 40 nM, p < 0.0001) and proliferation (35% reduction, p < 0.0001), with concomitant vWF mRNA upregulation (2.1-fold, p < 0.05).

CONCLUSION

Elevated circulating chemerin is associated with fetal endothelial dysfunction in GDM. Discordant mRNA/protein levels suggest post-transcriptional regulation. Cord blood chemerin may serve as a biomarker of fetal vascular injury, while fetal APV offers a non-invasive clinical tool. CMKLR1 antagonist studies are needed to establish therapeutic potential.