Persistent mechanical stretch-induced calcium overload and MAPK signal activation contributed to SCF reduction in colonic smooth muscle in vivo and in vitro |
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Authors: | Fang Dong Shu Yang Haimei Sun Jihong Yan Xiaoxia Guo Dandan Li |
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Affiliation: | 1. Department of Histology and Embryology, School of Basic Medical Sciences, Capital Medical University, Beijing, P. R. China;2. Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing, P. R. China;3. Experimental Teaching Center of Preclinical Medicine, Capital Medical University, Beijing, P. R. China |
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Abstract: | Gastrointestinal (GI) distention is a common pathological characteristic in most GI motility disorders (GMDs), however, their detail mechanism remains unknown. In this study, we focused on Ca2+ overload of smooth muscle, which is an early intracellular reaction to stretch, and its downstream MAPK signaling and also reduction of SCF in vivo and in vitro. We successfully established colonic dilation mouse model by keeping incomplete colon obstruction for 8 days. The results showed that persistent colonic dilation clearly induced Ca2+ overload and activated all the three MAPK family members including JNK, ERK and p38 in smooth muscle tissues. Similar results were obtained from dilated colon of patients with Hirschsprung's disease and stretched primary mouse colonic smooth muscle cells (SMCs). Furthermore, we demonstrated that persistent stretch-induced Ca2+ overload was originated from extracellular Ca2+ influx and endoplasmic reticulum (ER) Ca2+ release identified by treating with different Ca2+ channel blockers, and was responsible for the persistent activation of MAPK signaling and SCF reduction in colonic SMCs. Our results suggested that Ca2+ overload caused by smooth muscle stretch led to persistent activation of MAPK signaling which might contribute to the decrease of SCF and development of the GMDs. |
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Keywords: | Calcium overload colonic smooth muscle gastrointestinal motility disorder interstitial cell of Cajal MAPK signaling |
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