Characterizing the Endothelin System in Glaucoma
In order to ascertain whether these cells are harming blood vessels, they needed to localize other key components of the Endothelin system, including the receptors EDNRA and EDNRB. In the second year of funding, the team has shown that EDN2 is expressed in macrophages/microglia in the optic nerve head (Howell et al., 2012). They have shown that these cells are likely to infiltrate from the blood vessels very early in glaucoma. In addition, they showed that an FDA-approved drug, called Bosentan, can block the effects of EDN2 and protect mice from developing visible damage to their retina due to glaucoma. This drug is already used to treat pulmonary hypertension and chronic heart failure in humans. If proven effective in further laboratory and human clinical testing, this new Bosentan treatment could potentially prevent eye damage and vision loss due to glaucoma.
Two critical experiments are underway to continue to assess the importance of EDN2 in infiltrating macrophages/microglia. First, they are assessing glaucoma in DBA/2J mice that have an EDN2-deficient bone marrow (no EDN2 in the immune cells). Secondly, they are assessing glaucoma in mice that have been administered another type of Endothelin receptor antagonist drug. Further work is required to fully characterize the potential benefits of blocking the Endothelin system as a viable treatment for glaucoma.
Harmon K, Barbay JM, Porciatti V, Anderson MG, Smith RS, Clark AF, Libby RT and John SWM (2012). Radiation treatment inhibits monocyte entry into the optic nerve head and prevents glaucoma in DBA/2J mice. J. Clin. Invest. 122(4):1246-61.
Howell GR, Soto I, Zhu X, Ryan M, Macalinao DG, Sousa GL, Caddle LB, Harmon K, Barbay JM, Porciatti V, Anderson MG, Smith RS, Clark AF, Libby RT and John SWM (2012). Radiation treatment inhibits monocyte entry into the optic nerve head and prevents glaucoma in DBA/2J mice. J. Clin. Invest.
Reinholdt LG*, Howell GR*, Czechanski AM, Macalinao DG, MacNicoll KH, Lin C-S, Donahue LR and John SWMJ (2012). Generating embryonic stem cells from the inbred mouse strain DBA/2J, a model of glaucoma and other complex diseases. Plos One (in press).
*Authors contributed equally
First published on: April 1, 2010
Last modified on: March 21, 2013