Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews...
    • Mechanisms Underlying the Metabolic Syndrome (Oct 2019)
    • Reparative Immunology (Jul 2019)
    • Allergy (Apr 2019)
    • Biology of familial cancer predisposition syndromes (Feb 2019)
    • Mitochondrial dysfunction in disease (Aug 2018)
    • Lipid mediators of disease (Jul 2018)
    • Cellular senescence in human disease (Apr 2018)
    • View all review series...
  • Collections
    • Recently published
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Scientific Show Stoppers
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • About
  • Editors
  • Consulting Editors
  • For authors
  • Current issue
  • Past issues
  • By specialty
  • Subscribe
  • Alerts
  • Advertise
  • Contact
  • Conversations with Giants in Medicine
  • Author's Takes
  • Recently published
  • Brief Reports
  • Technical Advances
  • Commentaries
  • Editorials
  • Hindsight
  • Review series
  • Reviews
  • The Attending Physician
  • First Author Perspectives
  • Scientific Show Stoppers
  • Top read articles
  • Concise Communication
Sema3E-PlexinD1 signaling selectively suppresses disoriented angiogenesis in ischemic retinopathy in mice
Yoko Fukushima, … , Shin-Ichi Nishikawa, Akiyoshi Uemura
Yoko Fukushima, … , Shin-Ichi Nishikawa, Akiyoshi Uemura
Published May 2, 2011; First published April 18, 2011
Citation Information: J Clin Invest. 2011;121(5):1974-1985. https://doi.org/10.1172/JCI44900.
View: Text | PDF
Categories: Research Article Ophthalmology

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

  • Text
  • PDF
Abstract

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.

Authors

Yoko Fukushima, Mitsuhiro Okada, Hiroshi Kataoka, Masanori Hirashima, Yutaka Yoshida, Fanny Mann, Fumi Gomi, Kohji Nishida, Shin-Ichi Nishikawa, Akiyoshi Uemura

×

Figure 7

Intravitreal Sema3E injection selectively suppresses extraretinal vascular outgrowth without affecting vascular regeneration in ischemic retinas.

Options: View larger image (or click on image) Download as PowerPoint
Intravitreal Sema3E injection selectively suppresses extraretinal vascul...
(A and B) Whole-mount PECAM-1 IHC in OIR retinas of C57BL/6 mice at 24 hours (A) and 72 hours (B) after intravitreal injections of recombinant proteins (1 μl volume at 2 μg/μl concentration) at P14. Sema3E did not affect intraretinal projections of endothelial filopodia at P15 (A), but did suppress extraretinal vascular outgrowth at P17, leading to the restoration of normal vascular architecture in ischemic retinas (B). VEGFR1-Fc completely suppressed endothelial filopodia projections (A), resulting in extensive ischemic retinal areas (B). Scale bars: 10 μm (A); 100 μm (B). (C) Quantification of the number of extraretinal vessels, capillary density in the vascularized area, and unvascularized retinal area at 72 hours after injection of 1 μl recombinant proteins at P14. The protein concentrations (μg/μl) are indicated in the parentheses. P values were calculated by comparison with the Control Fc. Error bars represent SEM; ***P < 0.001, **P < 0.01.
Follow JCI:
Copyright © 2019 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts