Sema3E-PlexinD1 signaling selectively suppresses disoriented angiogenesis in ischemic retinopathy in mice

J Clin Invest. 2011 May;121(5):1974-85. doi: 10.1172/JCI44900. Epub 2011 Apr 18.


During development, the retinal vasculature grows toward hypoxic areas in an organized fashion. By contrast, in ischemic retinopathies, new blood vessels grow out of the retinal surfaces without ameliorating retinal hypoxia. Restoration of proper angiogenic directionality would be of great benefit to reoxygenize the ischemic retina and resolve disease pathogenesis. Here, we show that binding of the semaphorin 3E (Sema3E) ligand to the transmembrane PlexinD1 receptor initiates a signaling pathway that normalizes angiogenic directionality in both developing retinas and ischemic retinopathy. In developing mouse retinas, inhibition of VEGF signaling resulted in downregulation of endothelial PlexinD1 expression, suggesting that astrocyte-derived VEGF normally promotes PlexinD1 expression in growing blood vessels. Neuron-derived Sema3E signaled to PlexinD1 and activated the small GTPase RhoJ in ECs, thereby counteracting VEGF-induced filopodia projections and defining the retinal vascular pathfinding. In a mouse model of ischemic retinopathy, enhanced expression of PlexinD1 and RhoJ in extraretinal vessels prevented VEGF-induced disoriented projections of the endothelial filopodia. Remarkably, intravitreal administration of Sema3E protein selectively suppressed extraretinal vascular outgrowth without affecting the desired regeneration of the retinal vasculature. Our study suggests a new paradigm for vascular regeneration therapy that guides angiogenesis precisely toward the ischemic retina.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Vessels / pathology
  • Cell Adhesion Molecules, Neuronal / metabolism*
  • Cytoskeletal Proteins
  • Endothelial Cells / cytology
  • GTP Phosphohydrolases / metabolism
  • Glycoproteins / metabolism*
  • Humans
  • Hypoxia
  • Intracellular Signaling Peptides and Proteins
  • Ischemia / metabolism*
  • Ligands
  • Membrane Glycoproteins
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred ICR
  • Mice, Transgenic
  • Neovascularization, Pathologic / metabolism*
  • Nerve Tissue Proteins
  • Neurons / metabolism
  • Pseudopodia / metabolism
  • Retinal Diseases / metabolism*
  • Semaphorins
  • Signal Transduction*
  • Vascular Endothelial Growth Factor A / metabolism
  • rho GTP-Binding Proteins


  • Cell Adhesion Molecules, Neuronal
  • Cytoskeletal Proteins
  • Glycoproteins
  • Intracellular Signaling Peptides and Proteins
  • Ligands
  • Membrane Glycoproteins
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Plxnd1 protein, mouse
  • Rhoj protein, mouse
  • Sema3e protein, mouse
  • Semaphorins
  • Vascular Endothelial Growth Factor A
  • GTP Phosphohydrolases
  • rho GTP-Binding Proteins