The role of HIF-1, angiopoietin-2, Dll4 and Notch1 in bleeding gastrointestinal vascular malformations and thalidomide-associated actions: a pilot in vivo study

J Dig Dis. 2011 Oct;12(5):349-56. doi: 10.1111/j.1751-2980.2011.00506.x.

Abstract

Objective: To investigate plasma levels of hypoxia inducible factor-1 (HIF-1), angiopoietin-2 (Ang-2), Delta-like ligand 4 (Dll4) and Notch1 in patients with recurrent gastrointestinal bleeding due to gastrointestinal vascular malformation (GIVM) with or without thalidomide treatment.

Methods: Ten eligible patients with recurrent gastrointestinal bleeding due to GIVM, who received thalidomide 100 mg/d for 4 months, were followed up for 1 year. The effective response was the proportions of patients with yearly bleeding episodes reduced by ≥50% at 1 year after treatment. Plasma levels of HIF-1, Ang-2, Dll4 and Notch1 were measured using enzyme-linked immunosorbent assay in the GIVM thalidomide treatment group before and after treatment (10 patients), the GIVM non-thalidomide treatment group (25 patients) and the control group (18 participants).

Results: In the GIVM thalidomide treatment group, eight patients (8/10) achieved effective response and five (5/10) displayed complete cessation of bleeding. Mean plasma levels of HIF-1, Ang-2, Dll4 and Notch1 were all higher in the GIVM thalidomide and non-thalidomide treatment groups than in the control group (all P < 0.001). However, Ang-2 decreased more significantly in the effective subgroups (P = 0.003) and no-bleeding patients (P = 0.008).

Conclusions: HIF-1, Ang-2, Dll4 and Notch1 might participate in the formation of GIVM. Thalidomide is an effective and safe treatment agent for GIVM and its associated bleeding. The reduction degree of Ang-2 after a 4-month treatment of thalidomide may offer values for evaluating its prognosis and efficacy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Angiopoietin-2 / blood
  • Angiopoietin-2 / physiology*
  • Calcium-Binding Proteins
  • Gastrointestinal Hemorrhage
  • Humans
  • Hypoxia-Inducible Factor 1 / blood
  • Hypoxia-Inducible Factor 1 / physiology*
  • Intercellular Signaling Peptides and Proteins / blood
  • Intercellular Signaling Peptides and Proteins / physiology*
  • Pilot Projects
  • Receptor, Notch1 / blood
  • Receptor, Notch1 / physiology*
  • Recurrence
  • Thalidomide / therapeutic use*
  • Vascular Malformations / complications*
  • Vascular Malformations / drug therapy

Substances

  • Adaptor Proteins, Signal Transducing
  • Angiopoietin-2
  • Calcium-Binding Proteins
  • DLL4 protein, human
  • Hypoxia-Inducible Factor 1
  • Intercellular Signaling Peptides and Proteins
  • NOTCH1 protein, human
  • Receptor, Notch1
  • Thalidomide