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

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.

Corticotrophin-Releasing Factor, Related Peptides, and Receptors in the Normal and Inflamed Gastrointestinal Tract

“…One paper describes the expression of CRF1 in the distal colon of the ovine fetus, where it was expressed in muscle tissue, enteric ganglia, and goblet cells. Generally CRF1 immunoreactivity is seen to increase during gestation, especially in the enteric ganglia (Lakshmanan et al, 2008). Muramatsu et al (2000) showed CRF1 mRNA expression in human lamina propria mononuclear cells.…”

“…Another study did not report any CRF2 expression in the enteric plexuses of guinea pig (Bisschops et al, 2006). Finally, expression of CRF2, just like that of CRF1, was investigated in the ovine fetus: CRF2 expression in muscle layers was found to decrease with gestation, while neuronal expression was limited to fibers of unspecified origin (Lakshmanan et al, 2008). An overview of the colonic expression of CRF-related peptides is provided in Figure 3.…”

Differential stress-induced alterations of colonic corticotropin-releasing factor receptors in the Wistar Kyoto rat

“…CRFR1 is found in the enteric nervous system and the mucosal layer 14,19 of the gut and a recent report provided evidence that activation of these peripheral receptors could stimulate an increase in colonic motility, defecation, permeability and visceral pain sensation 17 . By contrast, activation of peripheral CRFR2, which has been detected in the mucosa, 14 mucosal inflammatory cells 20 and in enteric neurons, 21,22 induces inhibition of gastric emptying, suppresses stimulated colonic motor function and prevents the hypersensitivity to repeated colorectal distension (CRD) 23–25 . Furthermore, CRFR2 has been proposed to have a role in stress‐induced permeability dysfunction and the modulation of mucosal immune and inflammatory responses in the colon 26–28 …”

Mechanism(s) of in utero meconium passage

“…32 Our findings can be summarized as follows: CRF-R1-and CRF-R2-specific antibodies strongly immunostained longitudinal and circular smooth muscles in addition to muscularis mucosa in colonic segments at all gestational ages. A marked decrease in CRF-R2 immunostaining occurred in smooth muscle layers close to term.…”