PMID- 35619185
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20220716
IS  - 2045-3701 (Print)
IS  - 2045-3701 (Electronic)
IS  - 2045-3701 (Linking)
VI  - 12
IP  - 1
DP  - 2022 May 26
TI  - Fibronectin extra domain A (FN-EDA) causes glaucomatous trabecular meshwork, 
      retina, and optic nerve damage in mice.
PG  - 72
LID - 10.1186/s13578-022-00800-y [doi]
LID - 72
AB  - BACKGROUND: Elevated intraocular pressure (IOP) is a major risk factor for the 
      development and progression of primary open angle glaucoma and is due to 
      trabecular meshwork (TM) damage. Here, we investigate the role of an endogenous 
      Toll-like receptor 4 (TLR4) ligand, FN-EDA, in the development of glaucoma 
      utilizing a transgenic mouse strain (B6.EDA(+/+)) that constitutively expresses 
      only FN containing the EDA isoform. METHODS: Eyes from C57BL6/J (wild-type), 
      B6.EDA+/+ (constitutively active EDA), B6.EDA-/- (EDA null) mice were processed 
      for electron microscopy and consecutive images of the entire length of the TM and 
      Schlemm's canal (SC) from anterior to posterior were collected and montaged into 
      a single image. ECM accumulation, basement membrane length, and size and number 
      of giant vacuoles were quantified by ImageJ analysis. Tlr4 and Iba1 expression in 
      the TM and ONH cells was conducted using RNAscope in situ hybridization and 
      immunohistochemistry protocols. IOP was measured using a rebound tonometer, ON 
      damage assessed by PPD stain, and RGC loss quantified in RBPMS labeled retina 
      flat mounts. RESULTS: Ultrastructure analyses show the TM of B6.EDA(+/+) mice 
      have significantly increased accumulation of ECM between TM beams with few empty 
      spaces compared to C57BL/6 J mice (p < 0.05). SC basement membrane is thicker and 
      more continuous in B6.EDA(+/+) mice compared to C57BL/6 J. No significant 
      structural differences are detected in the TM of EDA null mice. Tlr4 and Iba1 
      expression is increased in the TM of B6.EDA(+/+) mice compared to C57BL/6 J eyes 
      (p < 0.05). IOP is significantly higher in B6.EDA(+/+) mice compared to C57BL/6 J 
      eyes (p < 0.001), and significant ON damage (p < 0.001) and RGC loss (p < 0.05) 
      detected at 1 year of age. Tlr4 mRNA is expressed in mouse ONH cells, and is 
      present in ganglion cell axons, microglia, and astrocytes. There is a significant 
      increase in the area occupied by Iba-1 positive microglia cells in the ONH of 
      B6.EDA(+/+) mice compared to C57BL/6 J control eyes (p < 0.01). CONCLUSIONS: 
      B6.EDA(+/+) mice have increased ECM accumulation in the TM, elevated IOP, 
      enhanced proinflammatory changes in the ONH, loss of RGCs, and ONH damage. These 
      data suggest B6.EDA(+/+) mice recapitulate many aspects of glaucomatous damage.
CI  - (c) 2022. The Author(s).
FAU - Mavlyutov, Timur A
AU  - Mavlyutov TA
AD  - Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, 
      Madison, WI, USA.
FAU - Myrah, Justin J
AU  - Myrah JJ
AD  - Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, 
      Madison, WI, USA.
FAU - Chauhan, Anil K
AU  - Chauhan AK
AD  - Department of Internal Medicine, Division of Hematology/Oncology, University of 
      Iowa, Iowa City, IA, USA.
FAU - Liu, Yang
AU  - Liu Y
AD  - Department of Pharmacology and Neuroscience, North Texas Eye Research Institute, 
      University of North Texas Health Science Center, Fort Worth, TX, USA.
FAU - McDowell, Colleen M
AU  - McDowell CM
AUID- ORCID: 0000-0001-9462-3556
AD  - Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, 
      Madison, WI, USA. cmmcdowell@wisc.edu.
LA  - eng
GR  - R01NS109910/NH/NIH HHS/United States
GR  - P30 EY016665/EY/NEI NIH HHS/United States
GR  - U01NS113388/NH/NIH HHS/United States
GR  - U01 NS113388/NS/NINDS NIH HHS/United States
GR  - R01EY02652/EY/NEI NIH HHS/United States
GR  - R35HL139926/NH/NIH HHS/United States
GR  - R01 EY026529/EY/NEI NIH HHS/United States
PT  - Journal Article
DEP - 20220526
PL  - England
TA  - Cell Biosci
JT  - Cell & bioscience
JID - 101561195
PMC - PMC9137085
OTO - NOTNLM
OT  - FN-EDA
OT  - Glaucoma
OT  - Optic nerve
OT  - Trabecular meshwork
COIS- The authors declare that they have no competing interests.
EDAT- 2022/05/27 06:00
MHDA- 2022/05/27 06:01
PMCR- 2022/05/26
CRDT- 2022/05/26 23:50
PHST- 2021/11/01 00:00 [received]
PHST- 2022/04/27 00:00 [accepted]
PHST- 2022/05/26 23:50 [entrez]
PHST- 2022/05/27 06:00 [pubmed]
PHST- 2022/05/27 06:01 [medline]
PHST- 2022/05/26 00:00 [pmc-release]
AID - 10.1186/s13578-022-00800-y [pii]
AID - 800 [pii]
AID - 10.1186/s13578-022-00800-y [doi]
PST - epublish
SO  - Cell Biosci. 2022 May 26;12(1):72. doi: 10.1186/s13578-022-00800-y.