Maternal Overweight Downregulates MME (Neprilysin) in Feto-Placental Endothelial Cells and in Cord Blood

Abstract

Maternal overweight in pregnancy alters the metabolic environment and generates chronic low-grade inflammation. This affects fetal development and programs the offspring’s health for developing cardiovascular and metabolic disease later in life. MME (membrane-metalloendopeptidase, neprilysin) cleaves various peptides regulating vascular tone. Endothelial cells express membrane-bound and soluble MME. In adults, the metabolic environment of overweight and obesity upregulates endothelial and circulating MME. We here hypothesized that maternal overweight increases MME in the feto-placental endothelium. We used primary feto-placental endothelial cells (fpEC) isolated from placentas after normal vs. overweight pregnancies and determined MME mRNA, protein, and release. Additionally, soluble cord blood MME was analyzed. The effect of oxygen and tumor necrosis factor α (TNFα) on MME protein in fpEC was investigated in vitro. Maternal overweight reduced MME mRNA (−39.9%, p < 0.05), protein (−42.5%, p = 0.02), and MME release from fpEC (−64.7%, p = 0.02). Both cellular and released MME protein negatively correlated with maternal pre-pregnancy BMI. Similarly, cord blood MME was negatively associated with pre-pregnancy BMI (r = −0.42, p = 0.02). However, hypoxia and TNFα, potential negative regulators of MME expression, did not affect MME protein. Reduction of MME protein in fpEC and in cord blood may alter the balance of vasoactive peptides. Our study highlights the fetal susceptibility to maternal metabolism and inflammatory state.

Increased expression of Neprilysin is associated with inflammation in Preeclampsia

“…Additionally, our study found an imbalance between pro-and anti-in ammatory cytokines, with proin ammatory cytokines (IL-6) being considerably higher in placental tissues of cases compared to controls and anti-in ammatory cytokines (IL-8) being signi cantly lower in cases compared to controls. In accordance with earlier studies, the outcomes of our study also showed a positive correlation between proin ammatory indicators and NEP (mRNA and protein) levels in patients compared to controls [12,13].…”

Neprilysin expression and functions in development, ageing and disease

“…3 ). On the other hand, maternal obesity was found to downregulate NEP expression in foetal-placental endothelium and in the umbilical cord blood which also may alter the balance of vasoactive peptides and affect foetal development and predispose the offspring to various metabolic diseases in later life ( Weiß et al, 2020 ).

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Silent hyperlipidaemia modulated vascular endothelial markers

“…The present study confirmed that early stages of hyperlipidemia might be associated with slight increase in plasma concentration of metalloendopeptidase enzyme and this could be a representative of progression of the hyperlipidemia to lipid deposition in sub-vascular spaces and also indicate leukocyte infiltration. Discrepant results have been reported by various studies regarding correlation between hyperlipidemia and increased plasma endopeptidases level; a study conducted by Weiß et al (2020), confirmed that the metalloendopeptidases elevated in hyperlipidemic patients.…”