期刊
FASEB JOURNAL
卷 30, 期 5, 页码 1968-1975出版社
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.201500057
关键词
cell senescence; fetal hypoxia; oxidative stress; allopurinol; xanthine oxidase
资金
- Royal Society
- MRC Metabolic Diseases Unit, Addenbrookes Hospital [MRC_MC_UU_12012/4]
- British Heart Foundation
- Wellcome Trust
- Perinatal Centre Wilhelmina Children's Hospital Utrecht
- Royal Dutch Academy of Sciences (Ter Meulen Fonds)
- Dutch Institute for Scientific Research
- Dutch Society of Obstetrics and Gynecology
- BBSRC [BB/E002668/1] Funding Source: UKRI
- MRC [MC_UU_12012/4] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [992201, BB/E002668/1] Funding Source: researchfish
- British Heart Foundation [FS/12/74/29778, PG/14/5/30547, PG/10/99/28656, RG/11/16/29260, FS/09/029/27902, RG/06/006/22028] Funding Source: researchfish
- Medical Research Council [MC_UU_12012/5, MC_UU_12012/4, MC_UU_12012/5/B] Funding Source: researchfish
Aging and developmental programming are both associated with oxidative stress and endothelial dysfunction, suggesting common mechanistic origins. However, their interrelationship has been little explored. In a rodent model of programmed cardiovascular dysfunction we determined endothelial function and vascular telomere length in young (4 mo) and aged (15 mo) adult offspring of normoxic or hypoxic pregnancy with or without maternal antioxidant treatment. We show loss of endothelial function [maximal arterial relaxation to acetylcholine (71 +/- 3 vs. 55 +/- 3%) and increased vascular short telomere abundance (4.2-1.3 kb) 43.0 +/- 1.5 vs. 55.1 +/- 3.8%) in aged vs. young offspring of normoxic pregnancy (P < 0.05). Hypoxic pregnancy in young off-spring accelerated endothelial dysfunction (maximal arterial relaxation to acetylcholine: 42 +/- 1%, P < 0.05) but this was dissociated from increased vascular short telomere length abundance. Maternal allopurinol rescued maximal arterial relaxation to acetylcholine 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 (vascular short telomere length abundance 35.1 +/- 2.5 vs. 48.2 +/- 2.6%) and of plasma proinflammatory chemokine (24.6 +/- 2.8 vs. 36.8 +/- 5.5 pg/ml, P < 0.05). These data provide evidence for divergence of mechanistic pathways mediating cardiovascular aging and developmental programming of cardiovascular disease, and aging being decelerated by antioxidants even prior to birth.-Allison, B.J., Kaandorp, J.J., Kane, A.D., Camm, E.J., Lusby, C., Cross, C.M., Nevin-Dolan, R., Thakor, A.S., Derks, J.B., Tarry-Adkins, J.L., Ozanne, S.E., Giussani, D.A. Divergence of mechanistic pathways mediating cardiovascular aging and developmental programming of cardiovascular disease. www.fasebj.org
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