The developmental origins of the metabolic syndrome have been established through the consistent observation that small-for-gestational age and large-for-gestational age fetuses have an increased risk for hypertension and related metabolic disorders later in life. These phenotypes have been reproduced in various species subjected to a range of intrauterine insults and ongoing research is directed towards understanding the underlying molecular mechanisms. Current evidence suggests that the creation of a pro-inflammatory and pro-oxidant intrauterine milieu is a common thread among prenatal factors that have an impact upon fetal size. Furthermore, studies demonstrate that a shift in fetal redox status consequent to environmental cues persists after birth and drives the progression of vascular dysfunction and hypertension in postnatal life. TLR (Toll-like receptor) signalling has emerged as a key link between inflammation and oxidative stress and a pathogenic contributor to hypertension, insulin resistance and obesity, in both human patients and animal models of disease. Thus TLR activation and dysregulation of its signalling components represent potential molecular underpinnings of programmed hypertension and related disorders in those subjected to suboptimal intrauterine conditions, yet their contributions to developmental programming remain unexplored. We propose that danger signals mobilized by the placenta or fetal tissues during complicated pregnancy activate the fetal innate immune system through TLRs and thereby potentiate the generation of ROS (reactive oxygen species) and orchestrate fetal adaptive responses, including changes in gene expression, which later translate to vascular dysfunction. Furthermore, we suggest that, after birth, continual activation of TLR signalling propagates vascular oxidative stress and thereby accelerates the advancement of hypertension and heart failure.
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March 13 2013
Potential role of Toll-like receptors in programming of vascular dysfunction
Jennifer A. Thompson;
1MCG Department of Physiology, Georgia Regents University, 1120 15th St, Augusta, GA 30912, U.S.A.
Correspondence: Dr Jennifer A. Thompson ([email protected]).
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R. Clinton Webb
R. Clinton Webb
1MCG Department of Physiology, Georgia Regents University, 1120 15th St, Augusta, GA 30912, U.S.A.
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Publisher: Portland Press Ltd
Received:
December 11 2012
Revision Received:
January 16 2013
Accepted:
February 04 2013
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© The Authors Journal compilation © 2013 Biochemical Society
2013
Clin Sci (Lond) (2013) 125 (1): 19–25.
Article history
Received:
December 11 2012
Revision Received:
January 16 2013
Accepted:
February 04 2013
Citation
Jennifer A. Thompson, R. Clinton Webb; Potential role of Toll-like receptors in programming of vascular dysfunction. Clin Sci (Lond) 1 July 2013; 125 (1): 19–25. doi: https://doi.org/10.1042/CS20120673
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