Journal Article

Hyaluronidase-1-mediated glycocalyx impairment underlies endothelial abnormalities in polypoidal choroidal vasculopathy

Ng, Chun Yi, Su, Xinyi, Cheung, Christine, Yang, Binxia, Chioh, Florence Wen Jing, Wu, Kan Xing, Hou, Han Wei, Narayanan, Gunaseelan, Tian, Xianfeng, Dunn, N. Ray, Yeo, Natalie Jia Ying, Fan, Qiao, Cheung, Chui Ming Gemmy, Tay, Hui Min

2022

Overview

Background Polypoidal choroidal vasculopathy (PCV), a subtype of age-related macular degeneration (AMD), is a global leading cause of vision loss in older populations. Distinct from typical AMD, PCV is characterized by polyp-like dilatation of blood vessels and turbulent blood flow in the choroid of the eye. Gold standard anti-vascular endothelial growth factor (anti-VEGF) therapy often fails to regress polypoidal lesions in patients. Current animal models have also been hampered by their inability to recapitulate such vascular lesions. These underscore the need to identify VEGF-independent pathways in PCV pathogenesis. Results We cultivated blood outgrowth endothelial cells (BOECs) from PCV patients and normal controls to serve as our experimental disease models. When BOECs were exposed to heterogeneous flow, single-cell transcriptomic analysis revealed that PCV BOECs preferentially adopted migratory-angiogenic cell state, while normal BOECs undertook proinflammatory cell state. PCV BOECs also had a repressed protective response to flow stress by demonstrating lower mitochondrial functions. We uncovered that elevated hyaluronidase-1 in PCV BOECs led to increased degradation of hyaluronan, a major component of glycocalyx that interfaces between flow stress and vascular endothelium. Notably, knockdown of hyaluronidase-1 in PCV BOEC improved mechanosensitivity, as demonstrated by a significant 1.5-fold upregulation of Krüppel-like factor 2 ( KLF2 ) expression, a flow-responsive transcription factor. Activation of KLF2 might in turn modulate PCV BOEC migration. Barrier permeability due to glycocalyx impairment in PCV BOECs was also reversed by hyaluronidase-1 knockdown. Correspondingly, hyaluronidase-1 was detected in PCV patient vitreous humor and plasma samples. Conclusions Hyaluronidase-1 inhibition could be a potential therapeutic modality in preserving glycocalyx integrity and endothelial stability in ocular diseases with vascular origin.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Abnormalities / Age / Age related diseases / Age-related macular degeneration / Aged / Analysis / Angiogenesis / Animal models / Biomedical and Life Sciences / Blood flow / Blood vessels / Care and treatment / Cell cycle / Cell migration / Choroid - blood supply / Choroid - pathology / Diagnosis / Endothelial Cells / Endothelial dysfunction / Endothelium / Eye diseases / Fluorescein Angiography / Genes / Genetic engineering / Glycocalyx / Glycocalyx - pathology / Growth factors / Health risk assessment / Humans / Hyaluronic acid / Hyaluronidase-1 / Hyaluronoglucosaminidase - genetics / Hyaluronoglucosaminidase - therapeutic use / Impairment / Inflammation / Interfaces / Krueppel-like factor / Lesions / Life Sciences / Macular degeneration / Macular Degeneration - drug therapy / Macular Degeneration - pathology / Medical imaging / Mitochondria / Pathogenesis / Permeability / Physics of Living Matter / Polypoidal choroidal vasculopathy / Polyps / Research Article / Risk factors / Shear stress / Transcription activation / Transcriptomics / Vascular diseases / Vascular endothelial growth factor / Vitreous humor / Vitreous humour / Yield strength