Colon motility disorders, especially problems associated with constipation and diarrhea, are common in adults and children, significantly affecting quality of life. New study in American Journal of Pathology, published by Elsevier, identifies neuropilin 2 (NRP2) as a new regulator of distal colon smooth muscle movement. Their ability to regulate cytoskeletal tone and to restrict abnormal smooth muscle contraction may provide opportunities in the future to inhibit or activate signals and thus regulate smooth muscle activity in patients with colonic motility disorders.
“Normal visceral smooth muscle activity is essential to the function of many body systems including the gastrointestinal tract and urinary tract, but it is much less studied than vascular smooth muscle,” explained co-author Maryrose P. Sullivan, Ph.D., Department of Surgery, Harvard Medical School; Department of Urology, VA Boston Healthcare System, Boston, MA, USA. “Previous studies by our group that demonstrated robust expression of Nrp2 in the smooth muscle of the colon led us to understand its functional importance in contraction and motility of the colon.”
The authors found an intense expression of NRP2 in the distal colon that was particularly prominent in circular and longitudinal smooth muscle in both human and mouse models. They used transgenic mice to determine the effect of Nrp2 deletion on colon contractility. Having demonstrated intense expression of Nrp2 in smooth muscle of the gastrointestinal tract, they identified the functional consequences of Nrp2 deletion of genes in the laboratory and analysis of motility in healthy mice. Their findings demonstrated that colon tissue exhibited an increased inducible contraction in mice with deletion of total or smooth muscle-specific Nrp2. Mice with inducible smooth muscle-specific Nrp2 deletion also showed increased colonic motility.
We were intrigued by the appearance of functional changes as early as a week after Nrp2 deletion. The relatively rapid detection of differences in the contractile behavior of the colonic muscle argues against major structural changes in tissues, but indicates changes in cellular signaling. Identification of Nrp2-regulated signaling networks in smooth muscle is a major focus of our ongoing research.”
Rosalynn Adam, Ph.D., associate principal investigator, Urology Research Center, Boston Children’s Hospital; and Department of Surgery, Harvard Medical School, Boston, Massachusetts, USA
Dr. Sullivan and Dr. Adam note that their study provides an important addition to understanding the mechanisms of visceral smooth muscle regulation and suggests that Nrp2 may be a practical target in diseases characterized by abnormal smooth muscle contraction.
“Although studies in patients are still a long way off, ongoing studies in our group focus on developing small molecule inhibitors designed to inhibit Nrp2. These efforts may provide opportunities in the future to inhibit signaling via Nrp2 and to regulate smooth muscle activity in patients. This has It is particularly relevant for diseases in which visceral smooth muscle is damaged, because effective pharmacological treatment for these conditions is not currently available.”
Changes in colon motility can result from a variety of conditions, including congenital malformations such as Hirschsprung’s disease, diabetes, inflammation, infection, intestinal dysbiosis, and nerve damage secondary to spinal injury. Furthermore, changes in the volume and/or coordination of systolic activity throughout the GI tract can lead to dyskinesia with disturbances in intestinal flora, inflammation, and nutrient absorption, often with serious health consequences.
Lambrinus, c. et al. (2022) Neuropilin 2 is a novel regulator of distal colonic contractility. American Journal of Pathology. doi.org/10.1016/j.ajpath.2022.07.013.