Regulation of Retinal Vascular Permeability by Betacellulin

  • Masahiko Sugimoto
  • Alecia Cutler
  • Gregory Grossman
  • Bela Anand-ApteEmail author
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 723)


Diabetic maculopathy, a leading cause of vision loss in patients with type 2 diabetes, is characterized by hyperpermeability of retinal blood vessels with subsequent formation of macular edema and hard exudates. Epidemiological studies have suggested that glycemic control plays a major role in the development of vascular complications of diabetes (Diabetes 42:1555–1558, 1993b). In an intervention cohort study, intensive treatment of diabetes reduced the development of proliferative diabetic retinopathy by 47% but was associated with a two to threefold increased risk of severe hypoglycemia (N Engl J Med 329:977–986, 1993a) and cardiovascular mortality. Therefore, it is critical to identify a downstream glycemic target that contributes to increased retinal vascular permeability that could be targeted therapeutically without the additional risks associated with intensive treatment of the hyperglycemia. Betacellulin is a 32 kDa member of the epidermal growth factor family that is produced by retinal pigment epithelial cells and Muller cells in addition to the proliferating β cells of the pancreatic islets and promotes regeneration of pancreatic β cells (Growth Factors 13:181–191, 1996; Endocrinol Metab 285:E577–583, 2003; Diabetes 53:608–615, 2004). Its mitogenic activity for smooth muscle cells and retinal pigment epithelial cells led us to hypothesize a role for betacellulin in the retinal vascular complications associated with diabetes (Science 259:1604–1607, 1993). Our studies (PLoS ONE 5:e13444, 2010) suggest that diabetic mice have accentuated retinal vascular permeability with a concomitant increased expression of a cleaved soluble form of betacellulin (s-Btc) in the retina. Intravitreal injection of betacellulin induced retinal hemorrhage and increased vascular permeability in normoglycemic and hyperglycemic mice. A disintegrin and metalloproteinase, ADAM-10 (which plays a role in the cleavage of betacellulin), is increased in the retinae of diabetic mice and humans with diabetic retinopathy. Based on these results, we hypothesize that betacellulin may contribute to increased retinal vascular permeability and the pathogenesis of diabetic macular edema.


Diabetic retinopathy Retinal vascular permeability Diabetic macular edema Betacellulin Epidermal growth factor receptor 


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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Masahiko Sugimoto
    • 1
  • Alecia Cutler
    • 1
  • Gregory Grossman
    • 1
  • Bela Anand-Apte
    • 1
    Email author
  1. 1.Department of Ophthalmology, Cole Eye InstituteCleveland Clinic Lerner College of Medicine at Case Western Reserve UniversityClevelandUSA

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