SCF-KIT signaling induces endothelin-3 synthesis and secretion: Thereby activates and regulates endothelin-B-receptor for generating temporally- and spatially-precise nitric oxide to modulate SCF- and or KIT-expressing cell functions

Abstract

We demonstrate that SCF-KIT signaling induces synthesis and secretion of endothelin-3 (ET3) in human umbilical vein endothelial cells and melanoma cells in vitro, gastrointestinal stromal tumors, human sun-exposed skin, and myenteric plexus of human colon post-fasting in vivo. This is the first report of a physiological mechanism of ET3 induction. Integrating our finding with supporting data from literature leads us to discover a previously unreported pathway of nitric oxide (NO) generation derived from physiological endothelial NO synthase (eNOS) or neuronal NOS (nNOS) activation (referred to as the KIT-ET3-NO pathway). It involves: (1) SCF-expressing cells communicate with neighboring KIT-expressing cells directly or indirectly (cleaved soluble SCF). (2) SCF-KIT signaling induces timely local ET3 synthesis and secretion. (3) ET3 binds to ETBR on both sides of intercellular space. (4) ET3-binding-initiated-ETBR activation increases cytosolic Ca2+, activates cell-specific eNOS or nNOS. (5) Temporally- and spatially-precise NO generation. NO diffuses into neighboring cells, thus acts in both SCF- and KIT-expressing cells. (6) NO modulates diverse cell-specific functions by NO/cGMP pathway, controlling transcriptional factors, or other mechanisms. We demonstrate the critical physiological role of the KIT-ET3-NO pathway in fulfilling high demand (exceeding basal level) of endothelium-dependent NO generation for coping with atherosclerosis, pregnancy, and aging. The KIT-ET3-NO pathway most likely also play critical roles in other cell functions that involve dual requirement of SCF-KIT signaling and NO. New strategies (e.g. enhancing the KIT-ET3-NO pathway) to harness the benefit of endogenous eNOS and nNOS activation and precise NO generation for correcting pathophysiology and restoring functions warrant investigation.

Arctiin alleviates functional constipation by enhancing intestinal motility in mice

“…Previous studies have ICC injury in the colons of patients and rats with FC (12,45). The present results revealed that C-Kit and SCF were mainly present in the submucosa and muscle layers, which is consistent with previous studies (46,47). Furthermore, a novel finding of the present study was that Arc prevented the increase in damage and increased the density of ICC in the colon of FC mice.…”

miR‑27a‑3p regulates the inhibitory influence of endothelin 3 on the tumorigenesis of papillary thyroid cancer cells

“…EDNs exert their functions by interacting with their cognate receptors (ETAR and ETBR), thus mediating fundamental processes in tissue differentiation, repair and growth ( 45 ). EDN1 and EDN3 primarily interact with ETAR and ETBR, respectively ( 46 ). EDN1 has been reported to be produced by endothelial cells, vascular smooth muscle cells, epithelial cells, hepatocytes and neurons ( 47 ).…”

“…By contrast, EDN3 primarily originates from epithelial cells, adrenal cells and neurons ( 48 ). By interacting with ETb, EDN3 frequently affects EDN1 autoinduction, angiogenesis, inflammatory pain, endothelin clearance and vasodilation ( 45 , 46 ).…”