PMID- 35164755
OWN - NLM
STAT- MEDLINE
DCOM- 20220414
LR  - 20220531
IS  - 1741-7007 (Electronic)
IS  - 1741-7007 (Linking)
VI  - 20
IP  - 1
DP  - 2022 Feb 15
TI  - Hyaluronidase-1-mediated glycocalyx impairment underlies endothelial 
      abnormalities in polypoidal choroidal vasculopathy.
PG  - 47
LID - 10.1186/s12915-022-01244-z [doi]
LID - 47
AB  - 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 Kruppel-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.
CI  - (c) 2022. The Author(s).
FAU - Wu, Kan Xing
AU  - Wu KX
AD  - Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, 
      Singapore.
FAU - Yeo, Natalie Jia Ying
AU  - Yeo NJY
AD  - Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, 
      Singapore.
FAU - Ng, Chun Yi
AU  - Ng CY
AD  - Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, 
      Singapore.
FAU - Chioh, Florence Wen Jing
AU  - Chioh FWJ
AD  - Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, 
      Singapore.
FAU - Fan, Qiao
AU  - Fan Q
AD  - Duke-NUS Medical School, National University of Singapore, Singapore, Singapore.
AD  - Ophthalmology & Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS 
      Medical School, Singapore, Singapore.
FAU - Tian, Xianfeng
AU  - Tian X
AD  - Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, 
      Singapore.
AD  - Duke-NUS Medical School, National University of Singapore, Singapore, Singapore.
FAU - Yang, Binxia
AU  - Yang B
AD  - Institute of Molecular and Cell Biology, Agency for Science, Technology and 
      Research, Singapore, Singapore.
FAU - Narayanan, Gunaseelan
AU  - Narayanan G
AD  - Institute of Medical Biology, Agency for Science, Technology and Research, 
      Singapore, Singapore.
FAU - Tay, Hui Min
AU  - Tay HM
AD  - School of Mechanical and Aerospace Engineering, Nanyang Technological University, 
      Singapore, Singapore.
FAU - Hou, Han Wei
AU  - Hou HW
AD  - Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, 
      Singapore.
AD  - School of Mechanical and Aerospace Engineering, Nanyang Technological University, 
      Singapore, Singapore.
FAU - Dunn, N Ray
AU  - Dunn NR
AD  - Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, 
      Singapore.
AD  - School of Biological Sciences Nanyang Technological University, Singapore, 
      Singapore.
AD  - Institute of Medical Biology, Agency for Science Technology and Research, 
      Singapore, Singapore.
FAU - Su, Xinyi
AU  - Su X
AD  - Institute of Molecular and Cell Biology, Agency for Science, Technology and 
      Research, Singapore, Singapore.
AD  - Department of Ophthalmology, Yong Loo Lin School of Medicine, National University 
      of Singapore, Singapore, Singapore.
AD  - Singapore Eye Research Institute, Singapore, Singapore.
AD  - Department of Ophthalmology, National University Hospital, Singapore, Singapore.
FAU - Cheung, Chui Ming Gemmy
AU  - Cheung CMG
AD  - Duke-NUS Medical School, National University of Singapore, Singapore, Singapore.
AD  - Singapore Eye Research Institute, Singapore, Singapore.
FAU - Cheung, Christine
AU  - Cheung C
AUID- ORCID: 0000-0001-7127-9107
AD  - Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, 
      Singapore. ccheung@ntu.edu.sg.
AD  - Institute of Molecular and Cell Biology, Agency for Science, Technology and 
      Research, Singapore, Singapore. ccheung@ntu.edu.sg.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220215
PL  - England
TA  - BMC Biol
JT  - BMC biology
JID - 101190720
RN  - EC 3.2.1.35 (Hyaluronoglucosaminidase)
SB  - IM
MH  - Aged
MH  - Choroid/blood supply/pathology
MH  - Endothelial Cells
MH  - Fluorescein Angiography
MH  - Glycocalyx/pathology
MH  - Humans
MH  - *Hyaluronoglucosaminidase/genetics/therapeutic use
MH  - *Macular Degeneration/drug therapy/pathology
PMC - PMC8845246
OTO - NOTNLM
OT  - Age-related macular degeneration
OT  - Endothelial dysfunction
OT  - Glycocalyx
OT  - Hyaluronidase-1
OT  - Polypoidal choroidal vasculopathy
COIS- The authors declare that they have no competing interests.
EDAT- 2022/02/16 06:00
MHDA- 2022/04/15 06:00
PMCR- 2022/02/15
CRDT- 2022/02/15 05:31
PHST- 2021/06/16 00:00 [received]
PHST- 2022/02/01 00:00 [accepted]
PHST- 2022/02/15 05:31 [entrez]
PHST- 2022/02/16 06:00 [pubmed]
PHST- 2022/04/15 06:00 [medline]
PHST- 2022/02/15 00:00 [pmc-release]
AID - 10.1186/s12915-022-01244-z [pii]
AID - 1244 [pii]
AID - 10.1186/s12915-022-01244-z [doi]
PST - epublish
SO  - BMC Biol. 2022 Feb 15;20(1):47. doi: 10.1186/s12915-022-01244-z.