Key result
Maternal methyl donor deficiency induces pathological aortic remodeling in aged rats, increasing elastin breaks ~9-fold.
Why the study?
Whether fetal programming provoked by maternal methyl donor deficiency causes long-term pathological effects on the aorta remained largely unknown.
Does fetal programming by methyl donor deficiency produce pathological remodeling of the ascending aorta in aged rats?
Does fetal programming by methyl donor deficiency produce pathological remodeling of the ascending aorta in aged rats?
Effect estimate: 8.7-fold increase
p-value: p=0.0002
Fetal programming by methyl donor deficiency causes irreversible pathological remodeling of the ascending aorta in aged rats, potentially explaining why adult vitamin B supplementation fails to relieve vascular complications.
Raises possibility of fetal nutritional programming in aortic disease; leaves open relevance to human methyl donor strategies.
Objective: Deficiency in vitamin B12/folate (methyl donor deficiency [MDD]) produces cardiovascular outcomes during aging and fetal programming effects in newborns of MDD mothers. Whether fetal programming provokes long-term effects on aorta remains largely unknown. Approach and Results: We investigated the impact of fetal programming on ascending aorta of aged rats born from mothers subjected to MDD during gestation/lactation. We performed morphological and molecular examinations of ascending aortas in 21 days- and 400 days-aged rats with initial MDD fetal programming (iMDD) compared with control matched rats. iMDD induces remodeling of the ascending aorta in aged rats, with collagen deposition ( P =0.0008), decreased thickness of elastin ( P <0.0001), and 8.7-fold increase of elastin breaks ( P =0.0002). Proteomic analyses, Western blotting, and immunohistochemical examination revealed decreased expression of α-smooth muscle actin, vinculin, SM22α (smooth muscle 22α), and N-cadherin and increased expression of TGF (transforming growth factor) β1. Elastin breaks were correlated to increased neutrophil elastase ( P =0.0002), cathepsin-K ( P =0.0002), cathepsin-S ( P <0.0001), MMP (matrix metalloproteinase) 9, and MMP2 ( P <0.0001 and P =0.02). Proximity Duolink ligation assay showed homocysteinylation of actin-associated and extracellular matrix proteins, including SM22α ( P =0.01), N-cadherin ( P =0.0008), and vinculin ( P =0.001), which was associated with elastin breaks ( P =0.002) and increased expression of MARS (methionyl-tRNA synthetase; involved in irreversible protein homocysteinylation). Furthermore, we observed an inverse relationship between elastin breaks and blood pressure (systolic, P =0.004 and diastolic, P =0.0007). Conclusions: MDD fetal programming produced altered integrity and remodeling of ascending aorta during aging and irreversible MARS-associated homocysteinylation of key proteins of extracellular matrix and elastin homeostasis. This contributes to understanding why homocysteine-lowering vitamin B supplementation fails to relieve vascular complications in adulthood.
No takes yet. Share an insight, caveat, or question.
Balint et al. (2021) studied Methyl donor deficiency fetal programming. Maternal methyl donor deficiency (vitamin B12/folate deficiency) vs. Control matched rats was evaluated on Elastin breaks in the ascending aorta (8.7-fold increase, p=0.0002). Fetal programming by maternal methyl donor deficiency induced pathological remodeling of the ascending aorta in aged rats, including an 8.7-fold increase in elastin breaks (P=0.0002).
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: