Abstract
Purpose: :
N-(4-hydroxyphenyl)retinamide (HPR) is a synthetic retinoid that halts the production of toxic fluorophores in occular tissue by reducing serum retinol. Importantly, HPR has also been reported to inhibit proliferation and prevent growth factor-mediated angiogenesis. HPR is currently in a phase II clinical trial for the treatment of geographic atrophy. While it is well tolerated and has a favorable toxicity profile, the role of HPR on angiogenesis in ocular tissue has not been resolved. Presently, we have designed a series of studies to address this issue.
Methods: :
The effect of HPR on ocular angiogenesis was assessed in three different models.1. The in vitro tube formation assay: Primary human retinal microvascular endothelial cells (HMRECs) were seeded on CultrexTM basement membrane extract (BME) after overnight exposure to HPR in the presence or absence of VEGF.2. The in vivo corneal micropocket assay: Standardized slow release pellets containing VEGF were surgically inserted into the normally avascular cornea of mice subjected to chronic HPR pretreatment.3. An animal model of retinal neovascularization: The extent of vascular leakage in the retina was assessed in the vldlr-/- mouse after chronic HPR pretreatment.
Results: :
HPR was found to reduce the severity of angiogenesis in all three models tested. For example, HPR inhibits the ability of HMRECs to form tubes on BME. In fact, we observe a significant reduction in tube formation by HMRECs exposed to VEGF in the presence of HPR. This finding indicates that HPR pretreatment counteracts the angiogenic effects of VEGF. HPR pretreatment also significantly reduced the extent of VEGF-induced neovascularization in the corneal micropocket assay. Finally, we observed a marked reduction in retinal vascular leakage in the vldlr-/- mouse following pretreatment with HPR.
Conclusions: :
Findings from the present study clearly demonstrate that HPR does not augment or exacerbate growth factor-mediated retinal pathology. Moreover, in animal models which manifest angiogenesis as part of "natural" retinal pathogenesis, HPR was found to ameliorate vascular leakage, consistent with previous findings of anti-angiogenic effects of HPR.
Keywords: neovascularization • age-related macular degeneration • vascular endothelial growth factor