Localization and gestation-dependent pattern of corticotrophin-releasing factor receptor subtypes in ovine fetal distal colon

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Abstract

Meconium passage is frequently observed in association with feto-maternal stress factors such as hypoxia and infection, but the triggering mechanism is unknown. We hypothesize that differential regulation of corticotrophin-releasing factor (CRF) receptors during gestation play an important role in determining the susceptibilities of the fetus to stress-induced in utero meconium passage at term. We examined the innervation patterns of CRF-receptor type 1 (CRF-R1), a stimulator of gastrointestinal motility and CRF-receptor type II (CRF-R2), an inhibitor of gastrointestinal motility in ovine fetal distal colonic segments from very preterm to term gestation. Both CRF-R1 and CRF-R2 receptors were present in muscularis mucosa as well as in longitudinal and circular smooth muscle layers in fetal distal colonic segments at all gestational ages. Quantitative image analysis indicated a 42% increase in CRF-R1 receptor immunoreactivity in muscularis mucosa and a 30% in longitudinal smooth muscle layers from very preterm to term. In contrast, CRF-R2 receptor immunoreactivity in muscularis mucosa as well as in longitudinal and circular smooth muscle layers decreased by 38%, 55% and 51%, respectively, at term. The percentage of enteric ganglia and the number of enteric neurons expressing CRF-R1 receptors were high at term. Western blot analysis identified 235 and 50 kDa molecular species of CRF-R1 receptors and 37 and 28 kDa molecular species of CRF-R2 receptors. In summary, we speculate that downregulation of CRF-R2 receptor abundance with concurrent increases in CRF-R1 receptor levels in myenteric-smooth muscle unit with advancing gestation sensitizes the colonic motility responses to stressors.

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