Fetal Programming by Methyl Donor Deficiency Produces Pathological Remodeling of the Ascending Aorta. Issue 6 (8th April 2021)

• Record Type: Journal Article
• Authors: Balint, Brittany; Hergalant, Sébastien; Camadro, Jean-Michel; Blaise, Sébastien; Vanalderwiert, Laetitia; Lignières, Laurent; Guéant-Rodriguez, Rosa-Maria; Guéant, Jean-Louis
• Is Part Of: Arteriosclerosis, thrombosis, and vascular biology. Volume 41:Issue 6(2021)
• Page Start: 1928
• Page End: 1941
• Publication Date: 2021-04-08
• Subjects: aorta -- blood pressure -- extracellular matrix -- homocysteine -- vinculin; Arteriosclerosis -- Periodicals; Thrombosis -- Periodicals; Blood-vessels -- Pathophysiology -- Periodicals; Electronic journals; 616.13
• DOI: 10.1161/ATVBAHA.120.315587
• Languages: English
• ISSNs: 1079-5642

Abstract

Abstract : Supplemental Digital Content is available in the text. Abstract : 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.