PMID- 32555351
OWN - NLM
STAT- MEDLINE
DCOM- 20201210
LR  - 20240426
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 10
IP  - 1
DP  - 2020 Jun 17
TI  - Fibronectin extra domain A (FN-EDA) elevates intraocular pressure through 
      Toll-like receptor 4 signaling.
PG  - 9815
LID - 10.1038/s41598-020-66756-6 [doi]
LID - 9815
AB  - 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, which leads to impaired aqueous humor outflow. Here, we explore a 
      novel molecular mechanism involved in glaucomatous TM damage. We investigated the 
      role of an endogenous Toll-like receptor 4 (TLR4) ligand, fibronectin-EDA 
      (FN-EDA), in TGFbeta2-induced ocular hypertension in mice. We utilized transgenic 
      mouse strains that either constitutively express only FN containing the EDA 
      isoform or contain an EDA-null allele and express only FN lacking EDA, with or 
      without a mutation in Tlr4, in our inducible mouse model of ocular hypertension 
      by injection of Ad5.TGFbeta2. IOP was measured over time and eyes accessed by 
      immunohistochemistry for total FN and FN-EDA expression. Constitutively active 
      EDA caused elevated IOP starting at 14 weeks of age. Ad5.TGFbeta2 induced ocular 
      hypertension in wildtype C57BL/6J mice and further amplified the IOP in 
      constitutively active EDA mice. TLR4 null and EDA null mice blocked 
      Ad5.TGFbeta-induced ocular hypertension. Total FN and FN-EDA isoform expression 
      increased in response to Ad5.TGFbeta2. These data suggest that both TLR4 and FN-EDA 
      contribute to TGFbeta2 induced ocular hypertension.
FAU - Roberts, Amanda L
AU  - Roberts AL
AD  - North Texas Eye Research Institute, Department of Pharmacology and Neuroscience, 
      University of North Texas Health Science Center, Fort Worth, Texas, United 
      States.
FAU - Mavlyutov, Timur A
AU  - Mavlyutov TA
AD  - Department of Ophthalmology and Visual Sciences, McPherson Eye Research 
      Institute, University of Wisconsin-Madison, Madison, WI, United States.
FAU - Perlmutter, Tanisha E
AU  - Perlmutter TE
AD  - Department of Ophthalmology and Visual Sciences, McPherson Eye Research 
      Institute, University of Wisconsin-Madison, Madison, WI, United States.
FAU - Curry, Stacy M
AU  - Curry SM
AD  - North Texas Eye Research Institute, Department of Pharmacology and Neuroscience, 
      University of North Texas Health Science Center, Fort Worth, Texas, United 
      States.
FAU - Harris, Sherri L
AU  - Harris SL
AD  - North Texas Eye Research Institute, Department of Pharmacology and Neuroscience, 
      University of North Texas Health Science Center, Fort Worth, Texas, United 
      States.
FAU - Chauhan, Anil K
AU  - Chauhan AK
AD  - Department of Internal Medicine, University of Iowa, Iowa City, IA, United 
      States.
FAU - McDowell, Colleen M
AU  - McDowell CM
AD  - Department of Ophthalmology and Visual Sciences, McPherson Eye Research 
      Institute, University of Wisconsin-Madison, Madison, WI, United States. 
      cmmcdowell@wisc.edu.
LA  - eng
GR  - P30 EY016665/EY/NEI NIH HHS/United States
GR  - R35 HL139926/HL/NHLBI NIH HHS/United States
GR  - U01 NS113388/NS/NINDS NIH HHS/United States
GR  - R01 HL118246/HL/NHLBI NIH HHS/United States
GR  - R01 HL118742/HL/NHLBI NIH HHS/United States
GR  - R25 GM125587/GM/NIGMS NIH HHS/United States
GR  - R01 EY026529/EY/NEI NIH HHS/United States
GR  - R01 NS109910/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20200617
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (Fibronectins)
RN  - 0 (Toll-Like Receptor 4)
RN  - 0 (Transforming Growth Factor beta2)
SB  - IM
MH  - Animals
MH  - Fibronectins/*chemistry/*metabolism
MH  - Gene Expression Regulation
MH  - *Intraocular Pressure
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - *Signal Transduction
MH  - Toll-Like Receptor 4/*metabolism
MH  - Trabecular Meshwork/cytology/metabolism
MH  - Transforming Growth Factor beta2/metabolism
PMC - PMC7299944
COIS- The authors declare no competing interests.
EDAT- 2020/06/20 06:00
MHDA- 2020/12/15 06:00
PMCR- 2020/06/17
CRDT- 2020/06/20 06:00
PHST- 2019/10/29 00:00 [received]
PHST- 2020/05/27 00:00 [accepted]
PHST- 2020/06/20 06:00 [entrez]
PHST- 2020/06/20 06:00 [pubmed]
PHST- 2020/12/15 06:00 [medline]
PHST- 2020/06/17 00:00 [pmc-release]
AID - 10.1038/s41598-020-66756-6 [pii]
AID - 66756 [pii]
AID - 10.1038/s41598-020-66756-6 [doi]
PST - epublish
SO  - Sci Rep. 2020 Jun 17;10(1):9815. doi: 10.1038/s41598-020-66756-6.