Semaphorin 5A promotes angiogenesis by increasing endothelial cell proliferation, migration, and decreasing apoptosis.
Semaphorin 5A (mouse, Sema5A; human, SEMA5A), is an axon regulator molecule and plays major roles during neuronal and vascular development. The importance of Sema5A during vasculogenesis, however, is unclear. The fact that Sema5A deficient mice display a defective branching of cranial vasculature supports its participation in blood vessel formation. In this study, we tested our hypothesis that Sema5A regulates angiogenesis by modulating various steps during angiogenesis. Accordingly, we demonstrated that the treatment of immortalized endothelial cells with recombinant extracellular domain of mouse Sema5A significantly increased endothelial cell proliferation and migration and decreased apoptosis. We also observed a relative increase of endothelial expression of anti-apoptotic genes relative to pro-apoptotic genes in Sema5A-treated endothelial cells suggesting its role in inhibition of apoptosis. In addition, our data suggest that Sema5A decreases apoptosis through activation of Akt, increases migration through activating Met tyrosine kinases and extracellular matrix degradation through matrix metalloproteinase 9. Moreover, in vivo Matrigel plug assays demonstrated that Sema5A induces endothelial cell migration from pre-existing vessels. In conclusion, the present work shows the pro-angiogenic role of Sema5A and provides clues on the signaling pathways that underlie them.
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198-5845, USA.
Anguraj
A
Sadanandam
Erin G
EG
Rosenbaugh
Seema
S
Singh
Michelle
M
Varney
Rakesh K
RK
Singh
D008841:Actin Cytoskeleton / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002460:Cell Line; D002465:Cell Movement; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D018919:Neovascularization, Physiologic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D019006:Neural Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D034622:RNA Interference; D017978:Receptors, Growth Factor / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D039961:Semaphorins; D015398:Signal Transduction; D013997:Time Factors; D051176:beta Catenin / Q000378:metabolism
C495270:CTNNB1 protein, human; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D019006:Neural Cell Adhesion Molecules; C496426:PLXNB3 protein, human; D017978:Receptors, Growth Factor; D011994:Recombinant Proteins; C103619:Sema5A protein, mouse; D039961:Semaphorins; D051176:beta Catenin; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D051057:Proto-Oncogene Proteins c-akt; D020780:Matrix Metalloproteinase 9