Roles of angiogenic factors and endothelin-1 in gastric ulcer healing

Abstract

Endothelins (ETs) participate directly and indirectly in angiogenesis via ET receptors. During early fetal angiogenesis, vascular endothelial growth factor (VEGF) and its receptors kinase insert domain-containing receptor (KDR) and fms-like tyrosine kinase-1 (Flt-1) are required for the development of the systemic vasculature. In late angiogenesis, stromal-cell-derived factor (SDF-1) and its receptor CXC chemokine receptor 4 (CXCR4) act in an organ-specific manner to promote the formation and development of large blood vessels supplying the gastrointestinal tract. We studied the roles of these ligand receptors in angiogenesis during healing of gastric ulcers. We studied the following five groups, each consisting of ten cases of endoscopically confirmed gastric ulcer: active stage (GA), healing stage (GH) and scar stage (GS) of gastric ulcers located in the angulus; Helicobacter pylori (Hp)-positive gastritis (gast+); and Hp-negative gastritis (gast-). All cases in the ulcer groups were Hp-positive. The study materials consisted of frozen biopsy specimens of lesions arising in the angulus. ET-1 was measured by enzyme immunoassay. The other factors were assayed by reverse-transcription-PCR. The distributions of ET-1, ETA receptor (ETAR), SDF-1 and CXCR4 in the gastric mucosa were evaluated by enzyme immunoassay. ET-1 and ETAR reached peak levels during the GH (ET: P<0.05, ETAR: P<0.01). VEGF mRNA increased slightly during the GA, but did not differ significantly among the groups. KDR and Flt-1 levels were high during the GA, the level being significantly higher than those during the GH and GS (P<0.05). SDF-1 levels significantly decreased during the GH and GS compared with levels during the GA, and CXCR4 significantly increased during the GH and GS (P<0.01). On immunostaining, ET-1-positive cells and ETAR-positive cells were found in the endothelium, vascular smooth muscle and gastric epithelium, and CXCR4-positive cells were found in the endothelium and gastric epithelium during the GH and GS. Our results suggest that VEGF receptors are mainly expressed early in ulcer development and participate in the initial stage of angiogenesis. SDF-1 receptors and ETAR are primarily expressed during the GH and GS and are involved in vascular maturation and gastric mucosal regeneration during late angiogenesis.

Antioxidant-mediated preventative effect of Dragon-pearl tea crude polyphenol extract on reserpine-induced gastric ulcers

“…Insufficient levels of Flt-1, a receptor of VEGF, may inhibit the generation of blood vessels in tissues (33). Thus, ulcer healing may be enhanced by increasing the expression of VEGF and Flt-1, to subsequently promote the regeneration of connective tissues, glands and the microvasculature, and dilute the harmful materials in the stomach to protect the gastric mucosa (34). The results of the present study indicate that DTCP may prevent gastric ulcers by increasing the expression levels of EGF, EGFR, VEGF and Flt-1, and reducing the expression of Gas.…”

CCL28 Is Increased in Human Helicobacter pylori -Induced Gastritis and Mediates Recruitment of Gastric Immunoglobulin A-Secreting Cells

“…Gastric memory B cells did not respond to any larger extent to CCL25 or CCL28, as we have previously reported for circulating memory B cells (21 (1,2). In another study, Mazzucchelli et al (29) showed a large production of CXCL13 (BCA-1) in H. pylori-induced gastritis that was localized mainly to the lymphoid follicles.…”

Secreted Trefoil Factor 2 Activates the CXCR4 Receptor in Epithelial and Lymphocytic Cancer Cell Lines

“…Indeed recombinant human TFF2 has been shown to be cytoprotective through in vivo models of gastric injury (23,59,60). In one study, during gastric ulcer healing, epithelial CXCR4 expres- sion levels were significantly increased, suggesting that CXCR4 might participate in the maintenance and renewal of the gastric epithelium (61). In the same study, SDF-1 levels were significantly down-regulated during ulcer healing, suggesting that another ligand (e.g.…”