|M.Sc Student||Alajem Adi|
|Subject||The Role of Semaphorin 3E in Angiogenesis|
|Department||Department of Medicine||Supervisor||Professor Emeritus Gera Neufeld|
Angiogenesis is an important process occurring in health and disease. Angiogenesis takes place during wound healing and in women during the monthly reproductive cycle and during pregnancy. Angiogenesis is controlled by a balance between proangiogenic and antiangiogenic factors. Both positive regulators and natural inhibitors of angiogenesis exist. In several major diseases such as in cancer, diabetic blindness, age-related macular degeneration, rheumatoid arthritis and psoriasis, the body loses control over angiogenesis. Angiogenesis-dependent diseases result when new blood vessels either grow excessively or insufficiently.
Semaphorins are a large family of transmembrane and secreted proteins. Semaphorins have been mainly described as inhibitory signals because they prevent cell migration and axon outgrowth, and lead to the ‘collapse’ of both pseudopodia and axonal growth cones. All semaphorins possess a Semaphorin domain at their amino termini and are divided into 8 classes based on species, amino acid sequence, and structural similarity.
Class-3 semaphorins are the only secreted semaphorins and include seven members. This class of semaphorins is distinguished by the presence of one immunoglobulin like domain and a basic amino acid rich region in addition to the Sema domain. Class 3 Semaphorins form active homodimers through formation of a disulfide bond in the basic rich region, which is critical for biological activity.
Signaling by semaphorin-3E and its receptor PlexinD1 controls the patterning of the developing vasculature in mice. Sema3E is highly expressed in developing somites, where it acts as a repulsive cue for PlexinD1-expressing endothelial cells. Sema3E-signaling does not require neuropilins, which had been presumed to be obligate Sema3 receptors and it binds directly to PlexinD1.
We have found that Sema3E inhibits the survival of human umbilical vein derived endothelial cells (HUVEC), as well as VEGF165 induced HUVEC proliferation. Sema3E expressing HEK293 cells repulse HUVEC and compromise their survival by the induction of apoptosis. These effects of Sema3E were not inhibited by siRNAs directed against neuropilins. Over-expression of Sema3E in HEK293 cells inhibited the formation of tumors from these cells in a chick embryo chorioallantoic membrane (CAM) tumor formation assay but did not inhibit the proliferation of the HEK293 cells in cell culture. The area surrounding the implantation site of Sema3E expressing cells in the CAM contained a lower concentration of blood vessels indicating that Sema3E is an inhibitor of tumor angiogenesis. A truncated form of Sema3E, previously reported to function as an inducer of tumor metastasis, was not active in these assays.