Glucocorticoids Promote Extracellular Matrix Component Remodeling by Activating YAP in Human Retinal Capillary Endothelial Cells

Abstract

Remodeling of extracellular matrix (ECM) components of endothelial cells is the main cause of retinal vascular basement membrane (BM) thickening, which leads to the initiation and perpetuation of microvasculopathy of diabetic retinopathy (DR). Excessive amounts of glucocorticoids (GCs) are related to the presence and severity of DR, however transcriptional effects of GCs on the biology of human retinal capillary endothelial cells (HRCECs) and its impacts on DR are still unclear. Here, we showed that GC (hydrocortisone) treatment induced ECM component [fibronectin (FN) and type IV collagen (Col IV)] expression and morphological changes in HRCECs via the glucocorticoid receptor (GR), which depended on the nuclear translocation of YAP coactivator. Mechanistically, GCs induced stress fiber formation in HRCECs, while blocking stress fiber formation inhibited GC-induced YAP nuclear translocation. Overexpression of FN, but not Col IV, activated YAP through the promotion of stress fiber formation via ECM-integrin signaling. Thus, a feedforward loop is established to sustain YAP activity. Using mRNA sequencing of HRCECs with overexpressed YAP or GC treatment, we found a similarity in Gene Ontology (GO) terms, differentially expressed genes (DEGs) and transcription factors (TFs) between the two RNA-seq datasets. In vivo, YAP was activated in retina vascular ECs of STZ-induced diabetic mice, and TF prediction analysis of published RNA-seq data of dermal vascular ECs from T2DM patients showed that GR and TEAD (the main transcription factor for YAP) were enriched. Together, GCs activate YAP and promote ECM component (FN and Col IV) remodeling in retinal capillary endothelial cells, and the underlying regulatory mechanism may provide new insights into the vascular BM thickening of the retina in the early pathogenesis of DR.

Diabetic vascular diseases: molecular mechanisms and therapeutic strategies

“… 248 , 249 Intraocular glucocorticoid injection is often used to treat persistent and refractory diabetic macular edema, which improves vision but increases the incidence of cataracts and glaucoma. 250 Drugs such as ranibizumab, aflibercept, and fenofibrate have been included in clinical trials to evaluate their effectiveness and safety (Table 3 ), thus providing new ideas for treating DR.…”

The Hippo signalling pathway and its impact on eye diseases

“…VEGF receptor activation inhibits LATS and activates YAP/TAZ to regulate VEGF‐induced retinal angiogenesis 48 . Several medications, such as the Chinese patent medicine Compound Xueshuantong Capsule, 23,52 folic acid 47 and glucocorticoids, 53,54 reverse retinal vascular dysfunction by inhibiting the YAP/TAZ pathway, thereby ameliorating diabetic macular edema and reducing the incidence of complications. These results suggest that YAP/TAZ may be a potential therapeutic target for DR.…”

Glucocorticoid-Induced Ocular Hypertension and Glaucoma

“…Recent studies have shown that YAP/TAZ signaling plays an important role in glaucoma-related ocular tissues including the lamina cribrosa, 67 retinal capillary endothelial cells, 68 and TM. 69–71 The cross-talk between YAP/TAZ and GR signaling in the TM may contribute to GIOHT/GIG.…”