Age-related macular degeneration (AMD) is a common condition that can lead to severe impairment of vision. In certain types of AMD, drusen bodies form in the eye, which are extracellular deposits of lipids, proteins and cellular debris. Drusen formation in AMD induces mechanical stress in the retinal pigment epithelial (RPE) cell layer, which upregulates VEGF and angiogenesis. Excessive angiogenesis is characteristic of AMD, but the molecular mechanisms by which mechanical stimulation induces VEGF production and angiogenesis in RPE cells in unclear.
Atsushige Ashimori, Kazuhiro Kimura and colleagues used in vitro and in vivo models of drusen-type AMD to unravel the mechanisms of mechanical stimulation in RPE cells. Firstly, they used human RPE1 cells cultured in stretch-stimulation chambers and found that 3 h of mechanical stimulation increased the production of VEGF as well as other angiogenesis-related factors, including ANG1, ANG2, IL6, IL8 and COL1A1. Interestingly, this upregulation of angiogenesis-related factors was abolished by pharmacological inhibition and siRNA knockdown of the transcription factor HIF-1α. The authors then added the supernatants from the mechanically stimulated RPE1 cells to vascular endothelial cells, which induced angiogenesis; this effect was also attenuated by pretreatment of the RPE1 cells with the HIF-1α inhibitor. Digging deeper into the mechanism, the authors found that pharmacological inhibition of tyrosine kinase SRC and p38 MAPK attenuated HIF-1α activation and the upregulation of the angiogenesis-related factors that was induced by mechanical stimulation in RPE1 cells. Finally, to validate these findings in vivo, the authors mimicked the mechanical stimulation caused by drusen formation during AMD by intraocular insertion of glass beads in mice. RPE cells from these eyes showed increased VEGF and ANG2 gene expression, which was prevented by intraocular injection of the HIF-1α inhibitor.
Overall, the authors used in vitro and in vivo models of drusen-type AMD to determine that mechanical stimulation induces angiogenesis and expression of angiogenesis-related factors in RPE cells via a SRC–p38–HIF-1α axis. This sheds light on the pathological mechanisms of drusen-type AMD and encourages further investigation of HIF-1α inhibitors as a potential treatment for pathological angiogenesis.
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