The role of angiomotin in angiogenesis

Abstract

Angiogenesis plays key roles during embryonic development, female reproduction and wound repair. Angiogenesis, the formation of new blood vessels from of pre-existing capillaries, is a process tightly regulated by a balance between positive and negative regulators. Unregulated angiogenesis may lead to several angiogenic diseases, and is thought to be crucial for tumor growth and metastasis. The initial recognition of tumor angiogenesis as a therapeutic target began in the 1970s, when Dr. J.Folkman hypothesized that cut-off of tumor blood vessels could be used as a target for cancer therapy. Since that time 20 angiogenesis inhibitors have been tested in clinical trials.

Recently it was announced that Avastin, a humanized antibody, designed to inhibit vascular endothelial growth factor (which plays a crucial role in tumor angiogenesis), significantly prolonged the time to progression of metastatic renal cell carcinoma. Angiostatin, an endogenous angiogenesis inhibitor, is being used in Phase II clinical trials. However, the mechanisms by which angiostatin inhibits angiogenesis are still not completely understood.

We have identified a novel protein, angiomotin, as an angiostatin-binding protein, that mediates angiostatin inhibitory effect on endothelial cell migration and tube formation. In vivo angiomotin is expressed in the endothelial cells of capillaries as well as larger vessels of human placenta. Expression of angiomotin in endothelial cells enchanced their motility and capillary-like tube formation.

Angiomotin is a member of a new protein family, characterized by conserved coiled-coil and PDZ-binding domains. We have shown that deletion of the c-terminal protein-recognition site of angiomotin resulted in a loss of responsiveness of migrating cells to chemotactic factors, a key process in cell migration. Transgenic mice, expressing the c-terminal deletion mutant of angiomotin were shown to have impaired blood vessel formation in the brain as well as in the inter-somatic regions.

We conclude that vascular abnormalities in mouse brain development were caused by an inability of endothelial cells to respond to chemotactic factors and migrate. The importance of angiomotin in cell motility was confirmed by another group, studying the molecular mechanisms of arterior visceral endoderm movement early during mouse embryogenesis. Angiomotin knockout mice exhibited abnormal visceral endoderm cell migration during gastrulation, resulting in early embryonic lethality.

Using a model of hemangioendothelioma in SCID mice we demonstrated that angiomotin promoted tumor growth by stimulation of invasion as well as by stabilization of newly formed vessels. Taken together, these results demonstrate the important role of angiomotin in the cell migratory machinery.

The identification of angiomotin partners as promoting of endothelial cell migration, as well as genes, regulated by angiosatin-angiomotin interactions, may have important implications in the development of anti-angiogenesis therapy. Using gene expression profiling techniques, a set of genes were found, that were involved in angiomotin-induced cell motility, including two members of Rho GTPases family, CD-2 related protein, glypican-1, transforming growth factor beta-receptor III, cathepsin B, troponin T2, insulin-like growth factor 2 and three angiostatin-related proteins- ELMO-1, semaphorin 3A and DVS-27 related protein. These data provide a new basis for further studies of the mechanisms of angiostatin-angiomotin interactions.