Betacellulin induces increased retinal vascular permeability in mice.
BACKGROUND
Diabetic maculopathy, the leading cause of vision loss in patients with type 2 diabetes, is characterized by hyper-permeability of retinal blood vessels with subsequent formation of macular edema and hard exudates. The degree of hyperglycemia and duration of diabetes have been suggested to be good predictors of retinal complications. Intervention studies have determined that while intensive treatment of diabetes reduced the development of proliferative diabetic retinopathy it was associated with a two to three-fold increased risk of severe hypoglycemia. Thus we hypothesized the need to identify downstream glycemic targets, which induce retinal vascular permeability that could be targeted therapeutically without the additional risks associated with intensive treatment of the hyperglycemia. Betacellulin is a 32 kD member of the epidermal growth factor family with mitogenic properties for the retinal pigment epithelial cells. This led us to hypothesize a role for betacellulin in the retinal vascular complications associated with diabetes.


RESULTS
In this study, using a mouse model of diabetes, we demonstrate 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 soluble betacellulin induced retinal vascular permeability in normoglycemic and hyperglycemic mice. Western blot analysis of retinas from patients with diabetic retinopathy showed an increase in the active soluble form of betacellulin. In addition, an increase in the levels of A disintegrin and metalloproteinase (ADAM)-10 which plays a role in the cleavage of betacellulin was seen in the retinas of diabetic mice and humans.


CONCLUSIONS
These results suggest that excessive amounts of betacellulin in the retina may contribute to the pathogenesis of diabetic macular edema.
Anand-Apte
Bela
B
Department of Ophthalmology, Cole Eye Institute, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio, United States of America. anandab@ccf.org
Ebrahem
Quteba
Q
Cutler
Alecia
A
Farage
Eric
E
Sugimoto
Masahiko
M
Hollyfield
Joe
J
Folkman
Judah
J
D000818:Animals; D066259:Betacellulin; D001813:Blood-Retinal Barrier; D002199:Capillary Permeability / Q000187:drug effects*; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D012171:Retinal Vessels / Q000187:drug effects*
C587851:BTC protein, human; D066259:Betacellulin; C587852:Btc protein, mouse; D036341:Intercellular Signaling Peptides and Proteins