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Folate deficiency promotes differentiation of vascular smooth muscle cells without affecting the methylation status of regulated genes.

Kolb, Andreas F.; Petrie, Linda; Mayer, Claus D.; Pirie, Lynn; Duthie, Susan J.


Andreas F. Kolb

Linda Petrie

Claus D. Mayer

Lynn Pirie


Elevated serum homocysteine, an intermediate of cellular one-carbon metabolism, is an independent risk factor for cardiovascular disease (CVD). Folate deficiency increases serum homocysteine and may contribute to CVD progression. Vascular smooth muscle cells (VSMCs) regulate vascular contractility, but also contribute to repair processes in response to vascular injury. Nutritional deficiencies, like folate deficiency, are thought to impact on this phenotypic plasticity, possibly by epigenetic mechanisms. We have investigated the effect of folate deficiency on VSMCs in two cell culture systems representing early and late stages of smooth muscle cells differentiation. We find that folate deficiency promotes differentiation towards a more contractile phenotype as indicated by increased expression of respective marker genes. However, microarray analysis identified markers of striated muscle as the predominant gene expression change elicited by folate deficiency. These changes are not merely a reflection of cell cycle arrest, as foetal calf serum restriction or iron deficiency do not replicate the gene expression changes observed in response to folate deficiency. Folate deficiency only has a marginal effect on global DNA methylation. DNA methylation of CpG islands associated with genes regulated by folate deficiency remains unaffected. This supports our earlier findings in a mouse model system which also did not show any changes in global DNA methylation in response to folate and vitamin B6/B12 deficiency. These data suggest that folate deficiency enhances the expression of smooth muscle marker gene expression, promotes a shift towards a skeletal muscle phenotype, and does not regulate gene expression via DNA methylation.


KOLB, A.F., PETRIE, L., MAYER, C.D., PIRIE, L. and DUTHIE, S.J. 2019. Folate deficiency promotes differentiation of vascular smooth muscle cells without affecting the methylation status of regulated genes. Biochemical journal [online], 476(19), pages 2769-2795. Available from:

Journal Article Type Article
Acceptance Date Sep 16, 2019
Online Publication Date Sep 17, 2019
Publication Date Oct 11, 2019
Deposit Date Sep 30, 2019
Publicly Available Date Sep 18, 2020
Journal Biochemical Journal
Print ISSN 0264-6021
Electronic ISSN 1470-8728
Publisher Portland Press
Peer Reviewed Peer Reviewed
Volume 476
Issue 19
Pages 2769-2795
Keywords B-vitamins; Folate; Vascular smooth muscle cells; DNA methylation; Gene regulation
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