Neuron-derived semaphorin 3A is an early inducer of vascular permeability in diabetic retinopathy via neuropilin-1

Cell Metab. 2013 Oct 1;18(4):505-18. doi: 10.1016/j.cmet.2013.09.003.


The deterioration of the inner blood-retinal barrier and consequent macular edema is a cardinal manifestation of diabetic retinopathy (DR) and the clinical feature most closely associated with loss of sight. We provide evidence from both human and animal studies for the critical role of the classical neuronal guidance cue, semaphorin 3A, in instigating pathological vascular permeability in diabetic retinas via its cognate receptor neuropilin-1. We reveal that semaphorin 3A is induced in early hyperglycemic phases of diabetes within the neuronal retina and precipitates initial breakdown of endothelial barrier function. We demonstrate, by a series of orthogonal approaches, that neutralization of semaphorin 3A efficiently prevents diabetes-induced retinal vascular leakage in a stage of the disease when vascular endothelial growth factor neutralization is inefficient. These observations were corroborated in Tg(Cre-Esr1)/Nrp1(flox/flox) conditional knockout mice. Our findings identify a therapeutic target for macular edema and provide further evidence for neurovascular crosstalk in the pathogenesis of DR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Animals
  • Cells, Cultured
  • Diabetes Mellitus, Experimental / chemically induced
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Experimental / pathology
  • Diabetic Retinopathy / metabolism*
  • Diabetic Retinopathy / pathology
  • Endothelial Cells / cytology
  • Endothelial Cells / drug effects
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Obese
  • Middle Aged
  • Neurons / metabolism*
  • Neuropilin-1 / deficiency
  • Neuropilin-1 / genetics
  • Neuropilin-1 / metabolism
  • Permeability / drug effects
  • RNA, Messenger / metabolism
  • Retina / metabolism
  • Retina / physiopathology
  • Semaphorin-3A / genetics
  • Semaphorin-3A / metabolism*
  • Semaphorin-3A / pharmacology
  • Vascular Endothelial Growth Factor A / pharmacology


  • RNA, Messenger
  • Semaphorin-3A
  • Vascular Endothelial Growth Factor A
  • Neuropilin-1