Blockade of Vascular Endothelial Growth Factor (VEGF) Aggravates the Severity of Acute Graft-versus-host Disease (GVHD) after Experimental Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT)

BACKGROUND: Recent clinical observation reported that there was a significant correlation between change in circulating vascular endothelial growth factor (VEGF) levels and the occurrence of severe acute graft-versus-host disease (GVHD) following allogeneic hematopoietic stem cell transplantation (allo-HSCT), but the action mechanisms of VEGF in GVHD have not been demonstrated. METHODS: This study investigated whether or not blockade of VEGF has an effect on acute GVHD in a lethally irradiated murine allo-HSCT model of B6 (H-2b)-->B6D2F1 (H-2b/d). Syngeneic or allogeneic recipient mice were injected subcutaneously with anti-VEGF peptides, dRK6 (50 microg/dose) or control diluent every other day for 2 weeks (total 7 doses). RESULTS: Administration of the dRK6 peptide after allo-HSCT significantly reduced survival with greaterclinical GVHD scores and body weight loss. Allogeneic recipients injected with the dRK6 peptide exhibited significantly increased circulating levels of VEGF and expansion of donor CD3+ T cells on day +7 compared to control treated animals. The donor CD4+ and CD8+ T-cell subsets have differential expansion caused by the dRK6 injection. The circulating VEGF levels were reduced on day +14 regardless of blockade of VEGF. CONCLUSION: Together these findings demonstrate that the allo-reactive responses after allo-HSCT are exaggerated by the blockade of VEGF. VEGF seems to be consumed during the progression of acute GVHD in this murine allo-HSCT model.

Effects of Anti-Vascular Endothelial Growth Factor (VEGF) on Pancreatic Islets in Mouse Model of Type 2 Diabetes Mellitus / 당뇨병

BACKGROUND: Vascular endothelial growth factor (VEGF) is associated with the development of diabetic complications. However, it is unknown whether systemic VEGF treatment has any effects on the pancreatic islets in an animal model of type 2 diabetes mellitus. METHODS: Anti-VEGF peptide (synthetic ATWLPPR, VEGF receptor type 2 antagonist) was injected into db/db mice for 12 weeks. We analyzed pancreatic islet morphology and quantified beta-cell mass. Endothelial cell proliferation and the severity of islet fibrosis were also measured. VEGF expression in isolated islets was determined using Western blot analysis. RESULTS: When anti-VEGF was administered, db/db mice exhibited more severe hyperglycemia and associated delayed weight gain than non-treated db/db mice. Pancreas weight and pancreatic beta-cell mass were also significantly decreased in the anti-VEGF-treated group. VEGF and VEGF receptor proteins (types 1 and 2) were expressed in the pancreatic islets, and their expression was significantly increased in the db/db group compared with the db/dm group. However, the elevated VEGF expression was significantly reduced by anti-VEGF treatment compared with the db/db group. The anti-VEGF-treated group had more prominent islet fibrosis and islet destruction than db/db mice. Intra-islet endothelial cell proliferation was also remarkably reduced by the anti-VEGF peptide. CONCLUSION: Inhibition of VEGF action by the VEGF receptor 2 antagonist not only suppressed the proliferation of intra-islet endothelial cells but also accelerated pancreatic islet destruction and aggravated hyperglycemia in a type 2 diabetes mouse model. Therefore, the potential effects of anti-VEGF treatment on pancreatic beta cell damage should be considered.

Clinical significance of serum vascular endothelial growth factor in Kawasaki disease / 소아과

PURPOSE: Kawasaki disease is a systemic vasculitis, leading cause of pediatric acquired heart disease. Vascular endothelial growth factor (VEGF) has functions as vascular permeability factor, plays an important role in coronary artery lesion (CAL). We studied the clinical significance of serum VEGF in Kawasaki disease. METHODS: Kawasaki group was 49 patients, and control group was 15 patients. Diagnosis followed AHA (American Heart Association) diagnostic criteria, with blood sampling in acute, subacute, and convalescent phase. Echocardiographic abnormalities were defined and the definition of intravenous gamma globulin (IVGG)-responsive and IVGG-resistant was determined. RESULTS: Serum VEGF of Kawasaki group was significantly higher than of control group. Comparison of serum VEGF between CAL and non-CAL group, between carditis group and non-carditis group showed no significant differences. Subacute serum VEGF was statistically higher in IVGG-resistant group than in IVGG-responsive group, and serum VEGF of IVGG-resistant group in subacute phase was statistically higher than in the other phases. Serum VEGF of convalescent CAL and non-CAL group in acute and subacute phase had meaningful differences. Total fever duration and subacute serum VEGF had positive correlation. Acute serum VEGF had positive correlation with ESR and CRP, all phases serum VEGF had also positive correlation with WBC. Acute and subacute serum VEGF had negative correlations with hemoglobin and albumin. CONCLUSION: Serum VEGF can help to determine the severity of Kawasaki disease, especially subacute serum VEGF seems to be used as a prognostic factor of coronary complication. Afterward, further studies needed with more strict diagnostic criteria and more study groups.