Potential role of toll-like receptors in programming of vascular dysfunction

Jennifer A. Thompson, R. Clinton Webb

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

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 therebyaccelerates the advancement of hypertension and heart failure.

Original languageEnglish (US)
Pages (from-to)19-25
Number of pages7
JournalClinical Science
Volume125
Issue number1
DOIs
StatePublished - Jul 1 2013

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Keywords

  • Developmental programming
  • Metabolic syndrome
  • Oxidative stress
  • Pro-inflammation
  • Toll-like receptor

ASJC Scopus subject areas

  • Medicine(all)

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