Extracellular-Matrix Mechanics Regulate the Ocular Physiological and Pathological Activities

Figure 2

Schematic effects induced by ECM stiffness and TGFβ regulating YAP/TAZ activity in HTM cells. (a) The increase in ECM stiffness promotes elevated intraocular pressure. (b) Ocular pathologic features of the eye with glaucoma compared to the normal eye. (c) Upregulation of ECM stiffness may regulate the formation of focal adhesion and actin skeleton rearrangement to improve YAP/TAZ activity and its nuclear translocation. Meanwhile, ECM stiffness activated TGFβ triggers ERK and ROCK signaling pathways, which also promotes the upregulation of YAP/TAZ activity. The transcription complex formed by YAP/TAZ and TEAD in the nucleus activates a variety of mechanically stimulated target genes (TGM2, FN, CRGF, PAI-1, vinculin, α-SMA, P-MLC, F-actin) to promote cell contractility and ECM remodeling in HTM, which can aggravate the tissue stiffness of HTM, lead to fibrotic phenotype, enhanced aqueous humor outflow resistance, increased IOP, and exacerbate the progression of glaucoma. In addition, the inhibition of the Wnt signaling pathway can promote RhoA to initiate downstream ECM stiffness-raising phenotype, finally leading to elevated IOP. CTGF: connective tissue growth factor. α-SMA: α-smooth muscle actin. COLA1: alpha-1 type I collagen. c-myc: the regulator genes and proto-oncogenes that code for transcription factors. TGM2: transglutaminase 2. P-MLC: phospho-myosin light chain. PAI-1: plasminogen activator inhibitor-1. F-actin: actin filaments. Vinculin: a membrane-cytoskeletal protein in focal adhesion plaques.