CD82 restrains pathological angiogenesis by altering lipid raft clustering and CD44 trafficking in endothelial cells.

Abstract

BACKGROUND:

Angiogenesis is crucial for many pathological processes and becomes a therapeutic strategy against diseases ranging from inflammation to cancer. The regulatory mechanism of angiogenesis remains unclear. Although tetraspanin CD82 is widely expressed in various endothelial cells (ECs), its vascular function is unknown.

METHODS AND RESULTS:

Angiogenesis was examined in Cd82-null mice with in vivo and ex vivo morphogenesis assays. Cellular functions, molecular interactions, and signaling were analyzed in Cd82-null ECs. Angiogenic responses to various stimuli became markedly increased upon Cd82 ablation. Major changes in Cd82-null ECs were enhanced migration and invasion, likely resulting from the upregulated expression of cell adhesion molecules such as CD44 and integrins at the cell surface and subsequently elevated outside-in signaling. Gangliosides, lipid raft clustering, and CD44-membrane microdomain interactions were increased in the plasma membrane of Cd82-null ECs, leading to less clathrin-independent endocytosis and then more surface presence of CD44.

CONCLUSIONS:

Our study reveals that CD82 restrains pathological angiogenesis by inhibiting EC movement, that lipid raft clustering and cell adhesion molecule trafficking modulate angiogenic potential, that transmembrane protein modulates lipid rafts, and that the perturbation of CD82-ganglioside-CD44 signaling attenuates pathological angiogenesis.

• Authors: Quan Wei, Feng Zhang, Mekel M Richardson, Nathan H Roy, William Rodgers, Yuechueng Liu, Wenyuan Zhao, Chenying Fu, Yingjun Ding, Chao Huang, Yuanjian Chen, Yao Sun, Lexi Ding, Yang Hu, Jian-Xing Ma, Michael E Boulton, Satish Pasula, Jonathan D Wren, Satoshi Tanaka, Xiaolin Huang, Markus Thali, Günter J Hämmerling, Xin A Zhang
• Journal: Circulation (Circulation) Vol. 130 Issue 17 Pg. 1493-504 (Oct 21 2014) ISSN: 1524-4539 [Electronic] United States
• PMID: 25149363 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 American Heart Association, Inc.

Chemical References

• Cd44 protein, mouse
• Cd82 antigen, mouse
• Cell Adhesion Molecules
• Gangliosides
• Hyaluronan Receptors
• Kangai-1 Protein

Topics

• Animals
• Cell Adhesion Molecules (metabolism)
• Cell Line
• Cell Movement (physiology)
• Cytoskeleton (metabolism)
• Endocytosis (physiology)
• Endothelial Cells (metabolism, pathology)
• Gangliosides (metabolism)
• Hyaluronan Receptors (metabolism)
• Kangai-1 Protein (genetics, metabolism)
• Membrane Microdomains (metabolism, pathology)
• Mice, Knockout
• Neovascularization, Pathologic (genetics, metabolism, pathology)
• Protein Transport (physiology)
• Signal Transduction (physiology)