TY - JOUR
T1 - Intravitreal Injection of TIMP3 or the EGFR inhibitor erlotinib offers protection from oxygen-induced retinopathy in mice
AU - Hewing, Nina Jasmin
AU - Weskamp, Gisela
AU - Vermaat, Joost
AU - Farage, Eric
AU - Glomski, Krzysztof
AU - Swendeman, Steven
AU - Paul Chan, Robison Vernon
AU - Chiang, Michael F.
AU - Khokha, Rama
AU - Anand-Apte, Bela
AU - Blobel, Carl Peter
PY - 2013/1
Y1 - 2013/1
N2 - Purpose. Pathological neovascularization is a crucial component of proliferative retinopathies. Previous studies showed that inactivation of A disintegrin and metalloproteinase 17 (ADAM17), a membrane-anchored metalloproteinase that regulates epidermal growth factor receptor (EGFR) signaling, reduces pathological retinal neovascularization in a mouse model of oxygen-induced retinopathy (OIR). Here, we tested how genetic inactivation of a physiological ADAM17 inhibitor, the tissue inhibitor of matrix metalloproteinases-3 (TIMP3), or intravitreal injection of TIMP3 or of the EGFR inhibitor erlotinib influenced the outcome of OIR. Methods. Wild-type mice were subjected to OIR in a chamber with 75% oxygen for 5 days beginning at postnatal day 7 (P7). Upon removal from the oxygen chamber at P12, they received a single intravitreal injection of TIMP3, erlotinib, or control. The central avascular area and neovascular tufts were measured after 5 days in room air (21% oxygen) at P17. Moreover, OIR experiments were performed with Timp3-/- mice and littermate controls. Results. Timp3-/- mice showed greater revascularization of the central avascular area and developed equal or fewer neovascular tufts compared to littermate controls, depending on the genetic background. Wild-type mice injected with TIMP3 or erlotinib developed fewer neovascular tufts when compared to untreated littermates. Moreover, vessel regrowth into the avascular area was reduced in TIMP3-injected mice, but not in erlotinib-injected mice. Conclusions. These studies demonstrate that TIMP3 and erlotinib inhibit pathological neovascularization in the mouse retina, most likely due to inactivation of ADAM17 and the EGFR, respectively. Thus, TIMP3 and erlotinib emerge as attractive candidate antiangiogenic compounds for prevention and treatment of proliferative retinopathies.
AB - Purpose. Pathological neovascularization is a crucial component of proliferative retinopathies. Previous studies showed that inactivation of A disintegrin and metalloproteinase 17 (ADAM17), a membrane-anchored metalloproteinase that regulates epidermal growth factor receptor (EGFR) signaling, reduces pathological retinal neovascularization in a mouse model of oxygen-induced retinopathy (OIR). Here, we tested how genetic inactivation of a physiological ADAM17 inhibitor, the tissue inhibitor of matrix metalloproteinases-3 (TIMP3), or intravitreal injection of TIMP3 or of the EGFR inhibitor erlotinib influenced the outcome of OIR. Methods. Wild-type mice were subjected to OIR in a chamber with 75% oxygen for 5 days beginning at postnatal day 7 (P7). Upon removal from the oxygen chamber at P12, they received a single intravitreal injection of TIMP3, erlotinib, or control. The central avascular area and neovascular tufts were measured after 5 days in room air (21% oxygen) at P17. Moreover, OIR experiments were performed with Timp3-/- mice and littermate controls. Results. Timp3-/- mice showed greater revascularization of the central avascular area and developed equal or fewer neovascular tufts compared to littermate controls, depending on the genetic background. Wild-type mice injected with TIMP3 or erlotinib developed fewer neovascular tufts when compared to untreated littermates. Moreover, vessel regrowth into the avascular area was reduced in TIMP3-injected mice, but not in erlotinib-injected mice. Conclusions. These studies demonstrate that TIMP3 and erlotinib inhibit pathological neovascularization in the mouse retina, most likely due to inactivation of ADAM17 and the EGFR, respectively. Thus, TIMP3 and erlotinib emerge as attractive candidate antiangiogenic compounds for prevention and treatment of proliferative retinopathies.
UR - http://www.scopus.com/inward/record.url?scp=84874723284&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84874723284&partnerID=8YFLogxK
U2 - 10.1167/iovs.12-10954
DO - 10.1167/iovs.12-10954
M3 - Article
C2 - 23299479
AN - SCOPUS:84874723284
SN - 0146-0404
VL - 54
SP - 864
EP - 870
JO - Investigative Ophthalmology and Visual Science
JF - Investigative Ophthalmology and Visual Science
IS - 1
ER -