Rodrigues M et al. (2016), Expression Pattern of HIF-1α and VEGF Supports ...

ECB-ART-45068

Invest Ophthalmol Vis Sci 2016 Dec 01;5715:6739-6746. doi: 10.1167/iovs.16-19513.

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Expression Pattern of HIF-1α and VEGF Supports Circumferential Application of Scatter Laser for Proliferative Sickle Retinopathy.

Rodrigues M , Kashiwabuchi F , Deshpande M , Jee K , Goldberg MF , Lutty G , Semenza GL , Montaner S , Sodhi A .

Abstract
Purpose: Retinal vascular occlusions in sickle cell anemia patients cause tissue ischemia and the release of angiogenic mediators that promote the development of retinal neovascularization, initiating proliferative sickle retinopathy (PSR). Laser photocoagulation (LPC) has emerged as the most common treatment for PSR. Nonetheless, only two randomized controlled clinical trials have evaluated the use of LPC for PSR, and both failed to definitively demonstrate efficacy of this approach. This may be due to a lack of knowledge regarding the appropriate location for placement of laser coagulations in PSR eyes. To help address this question, we examined the expression of hypoxia-inducible factor (HIF)-1α and vascular endothelial growth factor (VEGF) in PSR eyes. Methods: The expression pattern of HIF-1α and VEGF in PSR (n = 5) and control (n = 3) eyes was examined by immunohistochemistry in different retinal regions defined by the presence or absence of retinal vessels. Results: Hypoxia-inducible factor 1α and VEGF were expressed in the inner retina of 5/5 untreated PSR eyes adjacent to retinal neovascularization; expression of HIF-1α was not detected (and VEGF only lightly detected) in normal retinal and choroidal vasculature of 3/3 control eyes. Hypoxia-inducible factor 1α and VEGF were strongly expressed in retinal cells within avascular (nonperfused) retina, anterior to the boundary between perfused and nonperfused retina, as well as in posterior ischemic retina in the presence or absence of neovascular sea fans. Conclusions: If the goal of LPC in PSR is to quench the expression of HIF-1-driven angiogenic mediators, our results support broad application of peripheral laser for its treatment.

PubMed ID: 27951596
PMC ID: PMC5156513
Article link: Invest Ophthalmol Vis Sci
Grant support: [+]

Genes referenced: LOC100887844 LOC115919910 LOC115922368 nsmce2 vegfc

Article Images: [+] show captions

	Figure 2. Broad expression of GFAP in retinal Müller cells in the ischemic peripheral retina of PSR eyes. (A) Expression of GFAP in activated (injured) retinal Müller glial cells in ischemic peripheral retina extends anteriorly and posteriorly from the border between perfused (CD34+) and nonperfused (CD34−) retina. (B) Glial fibrillary acidic protein expression was observed in astrocytes but not retinal Müller cells in posterior (perfused) retina. Immunoglobulin G was used as a negative control. Similar results were obtained in 5/5 eyes with PSR.
	Figure 3. Expression of HIF-1α and VEGF in the different regions of peripheral retina of PSR eyes. (A) Ultra-widefield FA image from a patient with PSR with inset highlighting the different zones of retinal perfusion in the peripheral retina anterior and posterior to a retinal neovascular sea fan (yellow arrow) at the margin (blue line) between perfused and nonperfused retina (“marginal zone”; purple). The “transitional zone” (orange) between the marginal zone and the posterior perfused retina (red) has areas of capillary drop out (orange arrows) within areas of perfusion. (B) Expression of the endothelial cell marker CD34 (red), GFAP (green), and HIF-1α (purple) in perfused retina, “transitional zone,” and avascular retina. Expression of HIF-1α was detected in activated (GFAP-expressing) retinal Müller cells, microglial cells, and RPE cells in the transitional zone as well as in avascular retina (red arrows), but not in posterior (perfused) retina. Similar results were obtained in 5/5 PSR eyes.
	Figure 4. Expression of HIF-1α and VEGF in the peripheral retina of PSR eyes. Expression of HIF-1α and VEGF in avascular (nonperfused), marginal, and transitional zone distant from retinal NV. CD34 expression highlights the presence or absence of vascular endothelial cells and defines these zones.
	Figure 5. Peripheral vascular zones in patients with sickle cell retinopathy. (A) Ultra-widefield FA image from a patient with sickle cell retinopathy with inset highlighting the three zones of retinal perfusion in the peripheral retina anterior and posterior to the border (blue line) between perfused (P) and nonperfused retina (NP). The transitional zone (T) between the marginal zone (M) and the posterior perfused retina has areas of capillary drop out (white arrows) within areas of perfusion. (B) When a sickle cell patient presents with retinal NV (red arrow), treatment with LPC (Xs) is most commonly limited to the area immediately surrounding the retinal NV (white Xs). However, treatment of all three zones (marginal, nonperfused, and transitional; yellow Xs) may be required to quench the production of HIF-1–regulated angiogenic mediators in patients with sickle cell retinopathy. It remains to be determined whether additional treatment distal from the area of NV (red Xs) is also necessary to prevent progression despite local treatment. M, marginal zone: margin (2 mm) between nonperfused and transitional zone where retinal NV is most likely to occur; NP, nonperfused retina: complete loss of inner retinal vasculature; P, perfused retina: no capillary drop out; T, transitional zone: perfused retina posterior to marginal zone (2 mm) but with focal areas of capillary drop out (arrows).

References [+] :

Babapoor-Farrokhran, Angiopoietin-like 4 is a potent angiogenic factor and a novel therapeutic target for patients with proliferative diabetic retinopathy. 2015, Pubmed