An investigation into the role of Notch signaling, altered angiogenesis, and inflammatory-induced preterm delivery and related complications in Northeast Indian patients

Abstract

IntroductionNotch signaling is crucial during pregnancy with ability to regulate angiogenesis and inflammatory response. Considering the enigmatic importance of Notch signaling in pregnancy including placenta development, gestational disorders and adverse pregnancy; we performed experimental analysis to identify the Notch receptor-ligands association with Preterm delivery (PTD) and linked complication. MethodA total of 245 cases [Term n = 135 and Preterm n = 110] were enrolled for the study from Northeast Indian Population. The differential mRNA expression of Notch receptors , ligands, its downstream target Hes1 and Immune markers (IL-10, IL-12 and TNF-α) was studied by real time polymerase chain reaction. Further the protein study of Notch1 and 4, Hes1, VEGF and TNF-α was performed by immunofluorescence. ResultsPlacental mRNA expression of all the four notch receptors [Notch1 = 2.15 ± 1.02 fold, Notch2 = 6.85 ± 2.70 fold, and Notch3 = 1.74 ± 0.90 fold and Notch4 = 14.15 ± 6.72 fold]; ligands [JAG1 = 2.71 ± 1.22, JAG2 = 4.41 ± 2.31, DLL1 = 3.55 ± 1.38, DLL3 = 4.31 ± 2.82 and DLL4 = 3.07 ± 1.30 folds] and downstream target [Hes1 = 6.09 ± 2.89 folds] was elevated in PTD cases compared to Term delivery (TD) cases. The mRNA expression of pro-inflammatory marker (IL-12 = 3.99 ± 1.02 fold and TNF-α = 16.83 ± 2.97), was upregulated. The upregulated expression of Notch1(p < 0.001), JAG1 (p = 0.006), JAG2 (p = 0.009), DLL1 (p = 0.001), DLL4 (p < 0.001) Hes1 (p < 0.001), TNF-α (p < 0.001) and IL-12 (p = 0.006) were associated with the baby death; and Notch4 significantly inversely correlated with low birth weight (LBW). Consistently higher protein level expression of Notch1, Hes1, VEGFA and TNF-α was observed in preterm with highest expression in negative outcome cases. DiscussionTo conclude, the increased Notch1 expression and angiogenesis linked inflammation holds key in understanding the pathogenesis of PTD and linked complications and underlines its potential as therapeutic target for PTD interventions.