Divergence of mechanistic pathways mediating cardiovascular aging and developmental programming of cardiovascular disease
Federation of American Societies for Experimental Biology
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Allison, B., Kaandorp, J., Kane, A., Camm, E., Lusby, C., Cross, C., Nevin-Dolan, R., et al. (2016). Divergence of mechanistic pathways mediating cardiovascular aging and developmental programming of cardiovascular disease. FASEB Journal https://www.repository.cam.ac.uk/handle/1810/253782
Aging and developmental programming are both associated with oxidative stress and endothelial dysfunction, suggesting common mechanistic origins. However, their inter-relationship has been little explored. In a rodent model of programmed cardiovascular dysfunction we determined endothelial function and vascular telomere length in young (4 month) and aged (15 month) adult offspring of normoxic or hypoxic pregnancy with or without maternal antioxidant treatment. We show loss of endothelial function (maximal a rterial relaxation to acetylcholine, Achmax : 71±3 vs. 55±3%) and increased vascular short telomere abundance (VSTabund (4.2-1.3 kb) 43.0±1.5 vs. 55.1±3.8%) in aged versus young offspring of normoxic pregnancy (P<0.05). Hypoxic pregnancy in young offspring accelerated endothelial dysfunction (Achmax 42±1%, P<0.05) but this was dissociated from increased VSTabund. Maternal allopurinol rescued Achmax in aged offspring of normoxic or hypoxic pregnancy but not in young offspring of hypoxic pregnancy. Aged offspring of hypoxic allopurinol pregnancy compared with aged offspring of untreated hypoxic pregnancy had lower levels of short telomeres (VSTabund 35.1±2.5 vs. 48.2±2.6%) and of plasma KC/GRO (24.6±2.8 vs. 36.8±5.5 pg.ml-1, P<0.05). These data provide evidence for: 1) mediating cardiovascular aging and developmental programming of cardiovascular disease ; and 2) aging being decelerated by antioxidants even prior to birth.
aging, cell senescence, fetal hypoxia, oxidative stress, allopurinol, xanthine oxidase, antioxidant
The work was supported by The British Heart Foundation, The Wellcome Trust, The Perinatal Centre Wilhelmina Children’s Hospital Utrecht, The Royal Dutch Academy of Sciences (Ter Meulen Fonds), The Dutch Institute for Scientific Research (NWO) and The Dutch Society of Obstetrics and Gynecology (NVOG).
British Heart Foundation (FS/09/029/27902)
British Heart Foundation (RG/06/006/22028)
British Heart Foundation (PG/10/99/28656)
British Heart Foundation (RG/11/16/29260)
British Heart Foundation (FS/12/74/29778)
British Heart Foundation (PG/14/5/30547)
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Licence URL: http://creativecommons.org/licenses/by/4.0/