title: Inhibition of semaphorin as a novel strategy for therapeutic angiogenesis.
abstract: BACKGROUND
  The axon-guiding molecules known as semaphorins and their receptors (plexins) regulate the vascular pattern and play an important role in the development of vascular network during embryogenesis. Semaphorin (Sema)3E is one of the class 3 semaphorins, and plexinD1 is known to be its receptor. Although these molecules have a role in embryonic vascular development, it remains unclear whether the Sema3E/plexinD1 axis is involved in postnatal angiogenesis.
  
  
  OBJECTIVE
  The objective of this study was to elucidate the role of Sema3E/plexinD1 in postnatal angiogenesis.
  
  
  RESULTS
  Sema3E inhibited cell growth and tube formation by suppressing the vascular endothelial growth factor (VEGF) signaling pathway. Expression of Sema3E and plexinD1 was markedly upregulated in ischemic limbs of mice (2.5- and 4.5-fold increase for Sema3E and plexinD1, respectively), and inhibition of this pathway by introduction of the plexinD1-Fc gene or disruption of Sema3E led to a significant increase of blood flow recovery (1.6- and 1.5-fold increase for the plexinD1-Fc gene treatment and Sema3E disruption, respectively). Hypoxia activated the tumor suppressor protein p53, thereby upregulating Sema3E expression. Expression of p53 and Sema3E was enhanced in diabetic mice compared with normal mice (2- and 1.3-fold increase for p53 and Sema3E, respectively). Consequently, neovascularization after VEGF treatment was poor in the ischemic tissues of diabetic mice, whereas treatment with VEGF plus plexinD1-Fc markedly improved neovascularization.
  
  
  CONCLUSIONS
  These results indicate that inhibition of Sema3E may be a novel strategy for therapeutic angiogenesis, especially when VEGF is ineffective.
authors: Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
authors: Junji
authors: J
authors: Moriya
authors: Tohru
authors: T
authors: Minamino
authors: Kaoru
authors: K
authors: Tateno
authors: Sho
authors: S
authors: Okada
authors: Akiyoshi
authors: A
authors: Uemura
authors: Ippei
authors: I
authors: Shimizu
authors: Masataka
authors: M
authors: Yokoyama
authors: Aika
authors: A
authors: Nojima
authors: Mitsuhiro
authors: M
authors: Okada
authors: Hisashi
authors: H
authors: Koga
authors: Issei
authors: I
authors: Komuro
mesh_terms: D000818:Animals; D015153:Blotting, Western; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015870:Gene Expression; D006614:Hindlimb / Q000098:blood supply / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007511:Ischemia; D008562:Membrane Glycoproteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011993:Recombinant Fusion Proteins / Q000378:metabolism / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D039961:Semaphorins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D013311:Streptozocin; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C493082:PLXND1 protein, human; D011993:Recombinant Fusion Proteins; C494123:SEMA3E protein, human; D039961:Semaphorins; D016159:Tumor Suppressor Protein p53; D042461:Vascular Endothelial Growth Factor A; D013311:Streptozocin; D051058:Oncogene Protein v-akt; D048049:Extracellular Signal-Regulated MAP Kinases