RT Journal Article
SR Electronic
T1 Hyaluronidase-1-mediated glycocalyx impairment underlies endothelial abnormalities in polypoidal choroidal vasculopathy
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.10.06.463357
DO 10.1101/2021.10.06.463357
A1 Kan-Xing Wu
A1 Natalie Jia Ying Yeo
A1 Chun-Yi Ng
A1 Florence Wen Jing Chioh
A1 Fan Qiao
A1 Xianfeng Tian
A1 Yang Binxia
A1 Gunaseelan Narayanan
A1 Hui-Min Tay
A1 Han-Wei Hou
A1 N Ray Dunn
A1 Xinyi Su
A1 Chui Ming Gemmy Cheung
A1 Christine Cheung
YR 2021
UL http://biorxiv.org/content/early/2021/10/07/2021.10.06.463357.abstract
AB Background Polypoidal choroidal vasculopathy (PCV), a subtype of age-related macular degeneration (AMD), 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 through activation of Krüppel-like factor 2, a flow-responsive transcription factor, which in turn modulated 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.Competing Interest StatementThe authors have declared no competing interest.