Mechanical Regulation of Gene Expression in Gut Smooth Muscle Cells

Abstract

Intraluminal contents and their movement along the gastrointestinal tract create shear stress and mechanical stretch on the gut wall. While the shear stress is important in the initiation of immediate physiological responses, the circumferential mechanical stretch, such as that in obstructive bowel disorders, exerts long-lasting impacts on bowel functions by mainly affecting the deeper muscularis externae. Recent studies demonstrate that mechanical stretch alters gene transcription in gut smooth muscle cells (SMC), and the stretch-altered gene expression (mechano-transcription) may play a critical role in pathogenesis of motility dysfunction and abdominal pain in obstruction. Specifically, stretch-induced cyclo-oxygenase-2 and other pro-inflammatory mediators in gut SMC account for impairments of muscle contractility. Mechano-transcription of pain mediators such as nerve growth factor may contribute to visceral hypersensitivity, by sensitizing primary sensory neurons. This review aims to highlight the novel findings of mechano-transcription in the gut, and to discuss the signaling mechanisms and pathophysiological significance of mechano-transcription.

Microsomal Prostaglandin E Synthase-1 Plays a Critical Role in Long-term Motility Dysfunction after Bowel Obstruction

“…As shown previously 18 – 20 , 39 , mechano-transcription of COX-2 and COX-2 –derived PGE 2 in gut SMC play a critical role in motility dysfunction in obstruction. The present study suggests that the increased PGE 2 during bowel distention may further enhance the expression of mPGES-1, which contributes to the sustained increase of PGE 2 and long-term smooth muscle dysfunction even after distention is corrected.…”

“…The suppressed motility may account for symptoms such as nausea, vomiting, bloating, abdominal distention and constipation 2 , 12 – 14 , 18 , 30 . We discovered that lumen distention in BO leads to mechano-transcription of COX-2 and other pro-inflammatory mediators in gut smooth muscle 18 , 31 , 38 , 39 , and that the mechanical stress-induced COX-2 plays a critical role in the suppression of muscle contractility and motility function during the course of BO 18 , 20 , 38 , 39 .…”

Role of brain‐derived neurotrophic factor in the pathogenesis of distention‐associated abdominal pain in bowel obstruction

“…Previous studies found that circumferential mechanical stretch as encountered in BO initiates mechano‐transcription of COX‐2 and NGF as well in gut SMC. The mechanical stress‐induced gene expression of COX‐2, NGF, and BDNF in gut SMC plays critical roles in motility dysfunction and abdominal pain in obstruction . Taken together, these studies indicate that gut SMC, via the mechano‐transcription mechanism, has a unique role in the pathogenesis of gut dysfunction in obstructive bowel disorders.…”

“…The mechanical stress-induced gene expression of COX-2, NGF, and BDNF in gut SMC plays critical roles in motility dysfunction and abdominal pain in obstruction. 20,34,52 Taken together, these studies indicate that gut SMC, via the mechano-transcription mechanism, 52 has a unique role in the pathogenesis of gut dysfunction in obstructive bowel disorders. It is noteworthy that increased expression of COX-2 peaked on day 1 to day 3 of BO.…”

Novel Insights Into the Mechanisms of Abdominal Pain in Obstructive Bowel Disorders

“…Lumen distention is a cardinal characteristic of OBD ( Russell and Welch, 1990 ; Summers, 1999 ; Postier and Squires, 2007 ). It represents a circumferential stretch to the gut wall ( Shi, 2017 ). Mechanical stretch may play a key role in abdominal pain in chronic obstruction such as MBO, because medications to release distention also reduces abdominal pain ( Pandha and Waxman, 1996 ; Bicanovsky et al, 2006 ).…”