Pigment epithelium-derived factor protects retinal ganglion cells

BACKGROUND: Retinal ganglion cells (RGCs) are responsible for the transmission of visual signals to the brain. Progressive death of RGCs occurs in glaucoma and several other retinal diseases, which can lead to visual impairment and blindness. Pigment epithelium-derived factor (PEDF) is a potent antiangiogenic, neurotrophic and neuroprotective protein that can protect neurons from a variety of pathologic insults. We tested the effects of PEDF on the survival of cultured adult rat RGCs in the presence of glaucoma-like insults, including cytotoxicity induced by glutamate or withdrawal of trophic factors. RESULTS: Cultured adult rat RGCs exposed to glutamate for 3 days showed signs of cytotoxicity and death. The toxic effect of glutamate was concentration-dependent (EC(50 )= 31 μM). In the presence of 100 μM glutamate, RGC number decreased to 55 ± 4% of control (mean ± SEM, n = 76; P < 0.001). The glutamate effect was completely eliminated by MK801, an NMDA receptor antagonist. Trophic factor withdrawal also caused a similar loss of RGCs (54 ± 4%, n = 60, P < 0.001). PEDF protected against both insults with EC(50 )values of 13.6 ng/mL (glutamate) and 3.4 ng/mL (trophic factor withdrawal), respectively. At 100 ng/mL, PEDF completely protected the cells from both insults. Inhibitors of the nuclear factor κB (NFκB) and extracellular signal-regulated kinases 1/2 (ERK1/2) significantly reduced the protective effects of PEDF. CONCLUSION: We demonstrated that PEDF potently and efficaciously protected adult rat RGCs from glutamate- and trophic factor withdrawal-mediated cytotoxicity, via the activation of the NFκB and ERK1/2 pathways. The neuroprotective effect of PEDF represents a novel approach for potential treatment of retinopathies, such as glaucoma

Physiological and Pathological Vascular Aging

Aging is a risk factor for cardiovascular diseases. Through aging, blood vessels become stiffer, less elastic and, thus, with less ability to contract. The objectives of this chapter are to review (i) recent progresses in the characterization of physiological and pathological vascular aging and (ii) in vitro platforms to study vascular aging. Initially, we will discuss the causes and biomarkers of vascular aging. Then we will discuss the main characteristics related to physiological and pathological aging including (i) altered ECM remodeling (e.g. composition, mechanical properties, degradation, calcification of the ECM during aging), (ii) enhanced fibrosis (e.g. causes and mechanisms), (iii) vascular cell dysfunction triggered by chronic oxidative stress, inflammation or senescence, and (iv) altered responses of vascular cells to flow shear stress. Finally, we will discuss in vitro systems to study vascular aging, particularly the effect of biomechanics in aged cells as well as the effect of drugs during vascular aging