Journal article
Hydrogel cultures reveal Transient Receptor Potential Vanilloid 4 regulation of myofibroblast activation and proliferation in valvular interstitial cells
The FASEB journal, Vol.36(5), pp.e22306-n/a
05/2022
DOI: 10.1096/fj.202101863R
PMCID: PMC9009405
PMID: 35385164
Abstract
As aortic valve stenosis develops, valve tissue becomes stiffer. In response to this change in environmental mechanical stiffness, valvular interstitial cells (VICs) activate into myofibroblasts. We aimed to investigate the role of mechanosensitive calcium channel Transient Receptor Potential Vanilloid type 4 (TRPV4) in stiffness induced myofibroblast activation. We verified TRPV4 functionality in VICs using live calcium imaging during application of small molecule modulators of TRPV4 activity. We designed hydrogel biomaterials that mimic mechanical features of healthy or diseased valve tissue microenvironments, respectively, to investigate the role of TRPV4 in myofibroblast activation and proliferation. Our results show that TRPV4 regulates VIC proliferation in a microenvironment stiffness-independent manner. While there was a trend toward inhibiting myofibroblast activation on soft microenvironments during TRPV4 inhibition, we observed near complete deactivation of myofibroblasts on stiff microenvironments. We further identified Yes-activated protein (YAP) as a downstream target for TRPV4 activity on stiff microenvironments. Mechanosensitive TRPV4 channels regulate VIC myofibroblast activation, whereas proliferation regulation is independent of the microenvironmental stiffness. Collectively, the data suggests differential regulation of stiffness-induced proliferation and myofibroblast activation. Our data further suggest a regulatory role for TRPV4 regarding YAP nuclear localization. TRPV4 is an important regulator for VIC myofibroblast activation, which is linked to the initiation of valve fibrosis. Although more validation studies are necessary, we suggest TRPV4 as a promising pharmaceutical target to slow aortic valve stenosis progression.
Details
- Title: Subtitle
- Hydrogel cultures reveal Transient Receptor Potential Vanilloid 4 regulation of myofibroblast activation and proliferation in valvular interstitial cells
- Creators
- Dilara Batan - University of Colorado BoulderDouglas K Peters - University of Colorado BoulderMegan E Schroeder - University of Colorado BoulderBrian A Aguado - University of Colorado BoulderMark W Young - University of Colorado BoulderRobert M Weiss - University of IowaKristi S Anseth - University of Colorado Boulder
- Resource Type
- Journal article
- Publication Details
- The FASEB journal, Vol.36(5), pp.e22306-n/a
- DOI
- 10.1096/fj.202101863R
- PMID
- 35385164
- PMCID
- PMC9009405
- NLM abbreviation
- FASEB J
- ISSN
- 0892-6638
- eISSN
- 1530-6860
- Grant note
- R01 HL142935 / NHLBI NIH HHS R01 HL132353 / NHLBI NIH HHS R01 HL089260 / NHLBI NIH HHS R01 AI151636 / NIAID NIH HHS T32 HL007822 / NHLBI NIH HHS K99 HL148542 / NHLBI NIH HHS F32 HL137256 / NHLBI NIH HHS
- Language
- English
- Date published
- 05/2022
- Academic Unit
- Cardiovascular Medicine; Internal Medicine
- Record Identifier
- 9984359863102771
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