Abstract
Purpose :
Choroidal neovascularization (CNV) is a natural healing mechanism in order to replace lost choriocapillaris or to overcome hypoxia in AMD. It becomes a problem when the vessel formation is incomplete with subsequent leakage. By investigating histologically AMD donor eyes, we found a rescue of the photoreceptors over the CNV suggesting a protective role of these new non-leaky vessels. Therefore, we aim to stabilize developing blood vessels by using pigment epithelium derived factor (PEDF) in a rat model of VEGF induced CNV and in an ex vivo hypoxia model.
Methods :
For the generation and characterization of the in vivo rat CNV model, 2x109 AAV-VEGF-A165 particles were subretinally injected in 158 rat eyes. Six weeks later, a CNV was detected in 100% of the eyes using SLO/OCT as well as FA and ICG angiographies. 18 eyes were subsequently intravitreally injected with 5 µg of PEDF protein whereas 23 eyes without PEDF treatment served as controls. The eyes were evaluated in vivo and histologically one week later.
In addition, 12 isolated rat eyes were intravitreally injected with 10 µg of PEDF protein and then submitted to hypoxia for 15 hours. The presence of labyrinth capillaries which is the cause for leakage in wet AMD1 was investigated by histology.
1 Schraermeyer U et al: doi: 10.1007/s00417-014-2733-0.
Results :
In the in vivo model of CNV, a single injection of PEDF inhibited the progression of CNV. Ultrastructurally, the blood vessels growth was more coordinated. The vessels were associated with pericytes, were fenestrated and located directly below the RPE only separated by a newly formed Bruch's membrane. PEDF had strong stabilizing effects on the cellular junctions of retinal and choroidal capillaries and on the junctions of RPE cells. After PEDF treatment, even the choriocapillaris formed tight junctions.
In the ex vivo model, PEDF completely inhibited the formation of labyrinth capillaries.
Conclusions :
Choroidal vessel leakage is induced by a specific vessel type called labyrinth capillary which has open endothelial junctions and which is the cause for leakage in wet AMD (Fig. 1) PEDF inhibits the formation of this disastrous type of vessel in CNV. It inhibits uncontrolled vessel growth and due to its neuroprotective and vessel stabilizing role, PEDF is an ideal candidate to be used alone or synergistically with anti-VEGF treatments in order to stabilize instead to inhibit vessel growth in wet AMD.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.