Fetal Programming by Methyl Donor Deficiency Produces Pathological Remodeling of the Ascending Aorta

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 alpha-smooth muscle actin, vinculin, SM22 alpha (smooth muscle 22 alpha), and N-cadherin and increased expression of TGF (transforming growth factor) beta 1. 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 (PP=0.02). Proximity Duolink ligation assay showed homocysteinylation of actin-associated and extracellular matrix proteins, including SM22 alpha (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.

Automated summary

The study explores the impact of MDD fetal programming on the ascending aorta in aged rats, revealing significant alterations in structure and integrity, especially in elastin breaks which are inversely correlated with blood pressure. These findings contribute to understanding why homocysteine-lowering vitamin B supplementation fails to alleviate vascular complications in adulthood.