Inhibition of endothelial Slit2/Robo1 signaling by thalidomide restrains angiogenesis by blocking the PI3K/Akt pathway.

Abstract

BACKGROUND:

Thalidomide is effective in the treatment of angiodysplasia. The mechanisms underlying its activity may be associated with inhibition of angiogenic factors. It was recently shown that Slit2/Robo1 signaling plays a role in angiogenesis.

PURPOSE:

The aim of this study was to explore the expression and effects of Robo1 and Slit2 in angiodysplasia and to identify the possible therapeutic mechanisms of thalidomide.

METHOD:

Slit2 and Robo1 expression were analyzed in tissue samples and human umbilical vein endothelial cells (HUVECs) treated with thalidomide using a combination of laboratory assays that were able to detect functional activity.

RESULTS:

Slit2, Robo1 and vascular endothelial growth factor (VEGF) were strongly expressed in five angiodysplasia lesions out of seven cases, while expression was low in one out of seven normal tissues. Exposure of HUVECs to recombinant N-Slit2 resulted in an increase in VEGF levels and stimulated proliferation, migration and tube formation. These effects were blocked by an inhibitor of PI3K and thalidomide.

CONCLUSIONS:

Robo1 and Slit2 may have important roles in the formation of gastrointestinal vascular malformation. High concentrations of Slit2 increased the levels of VEGF in HUVECs via signaling through the PI3K/Akt pathway-an effect that could be inhibited by thalidomide.

• Authors: Yinan Li, Sengwang Fu, Haiying Chen, Qian Feng, Yunjie Gao, Hanbing Xue, Zhizheng Ge, Jingyuan Fang, Shudong Xiao
• Journal: Digestive diseases and sciences (Dig Dis Sci) Vol. 59 Issue 12 Pg. 2958-66 (Dec 2014) ISSN: 1573-2568 [Electronic] United States
• PMID: 25326112 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• Chromones
• Intercellular Signaling Peptides and Proteins
• Morpholines
• Nerve Tissue Proteins
• Receptors, Immunologic
• Vascular Endothelial Growth Factor A
• roundabout protein
• 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
• Thalidomide
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins c-akt
• Slit homolog 2 protein

Topics

• Angiogenesis Inhibitors (pharmacology)
• Cells, Cultured
• Chromones (pharmacology)
• Endothelial Cells (drug effects, metabolism)
• Gene Expression Regulation (drug effects)
• Humans
• Intercellular Signaling Peptides and Proteins (genetics, metabolism)
• Morpholines (pharmacology)
• Neovascularization, Physiologic (drug effects)
• Nerve Tissue Proteins (genetics, metabolism)
• Phosphatidylinositol 3-Kinases (genetics, metabolism)
• Proto-Oncogene Proteins c-akt (genetics, metabolism)
• Receptors, Immunologic (genetics, metabolism)
• Signal Transduction
• Thalidomide (pharmacology)
• Vascular Endothelial Growth Factor A (genetics, metabolism)