Role of angiopoietin-tie2 system in ocular vascular diseases

Abstract

Part I. Role of Angiopoietin-Tie2 System in Schlemm’s Canal Integrity and Glaucomagenesis Elevated intraocular pressure (IOP) because of increased resistance to aqueous humor outflow (AHO) is a main cause of primary open-angle glaucoma (POAG), however its pathogenesis is poorly understood. Here, I demonstrate that angiopoietin (Angpt)-Tie2 signaling, which is critical for formation of Schlemm’s canal (SC), is also indispensable for maintaining SC integ-rity during adulthood. Deletion of double Angpt1/Angpt2 or Tie2 in adult mice severely im-pairs SC integrity and transcytosis, leading to elevated IOP, retinal neuron damage, and im-pairment of retinal ganglion cell function, all POAG hallmarks. SC integrity is maintained by interconnected and coordinated roles of Angpt-Tie2 signaling, AHO, and Prox1 activity. These roles diminish in the SC during aging, leading to impaired integrity and transcytosis. Intriguingly, Tie2 re-activation using a Tie2 agonistic antibody rescues the POAG phenotype in double Angpt1-/Angpt2-deleted mice and rejuvenates the SC in aged mice. These results indicate that the Angpt-Tie2 system is essential for SC integrity. The impairment of this system reflects POAG-associated pathogenesis, and Tie2 agonists could be a therapeutic option for glaucoma.

Part II. Role of Angiopoietin-Tie2 System in Choriocapillary Maintenance and Neovascular Age-related Macular Degeneration Loss of the choriocapillaris, the principal blood supply to the outer retina, is a main initiator of neovascular age-related macular degeneration (NV-AMD). Although repeated administration of vascular endothelial growth factor (VEGF) blockade is overwhelmingly employed to treat NV-AMD, it leads only to temporary relief, and exacerbates choriocapillary rarefaction. Therefore, an advanced treatment for fundamental recovery of NV-AMD is required. Here, I demonstrate that angiopoietin (Angpt)-Tie2 signaling is essential for the maintenance of the choriocapillaris during adulthood. Conditional deletion of Tie2 in adult mice severely impedes choriocapillary maintenance, rendering eyes susceptible to the development of NV-AMD. Moreover, in a side-by-side comparison of intravitreal ABTAA (Angpt2-Binding and Tie2-Activating Antibody) and VEGF-Trap in a NV-AMD mouse model, I show that ABTAA not only suppresses choroidal neovascularization (CNV) and its vascular leakage but also regenerates the choriocapillaris and relieves hypoxia in the avascular space surrounding the CNV. Conversely, VEGF blockade degenerates the choriocapillaris and exacerbates hypoxia although it suppresses CNV and its vascular leakage. Together, my findings establish that Angpt-Tie2 signaling is critical for choriocapillary maintenance, and Tie2 activation by AB-TAA provides a fundamental therapeutic strategy to treat patients with NV-AMD without these adverse effects.