The role of valvular endothelial cell paracrine signaling and matrix elasticity on valvular interstitial cell activation

Sarah T Gould; Emily E Matherly; Jennifer N Smith; Donald D Heistad; Kristi S Anseth

doi:10.1016/j.biomaterials.2014.01.005

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The role of valvular endothelial cell paracrine signaling and matrix elasticity on valvular interstitial cell activation

Journal article

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The role of valvular endothelial cell paracrine signaling and matrix elasticity on valvular interstitial cell activation

Sarah T Gould, Emily E Matherly, Jennifer N Smith, Donald D Heistad and Kristi S Anseth

Biomaterials, Vol.35(11), pp.3596-3606

04/2014

DOI: 10.1016/j.biomaterials.2014.01.005

PMCID: PMC4040249

PMID: 24462357

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Abstract

The effects of valvular endothelial cell (VlvEC) paracrine signaling on VIC phenotype and nodule formation were tested using a co-culture platform with physiologically relevant matrix elasticities and diffusion distance. 100 μm thin poly(ethylene glycol) (PEG) hydrogels of 3–27 kPa Young's moduli were fabricated in transwell inserts. VICs were cultured on the gels, as VIC phenotype is known to change significantly within this range, while VlvECs lined the underside of the membrane. Co-culture with VlvECs significantly reduced VIC activation to the myofibroblast phenotype on all gels with the largest percent decrease on the 3 kPa gels (∼70%), while stiffer gels resulted in approximately 20–30% decrease. Additionally, VlvECs significantly reduced αSMA protein expression (∼2 fold lower) on both 3 and 27 kPa gels, as well as the number (∼2 fold lower) of nodules formed on the 27 kPa gels. Effects of VlvECs were prevented when nitric oxide (NO) release was inhibited with l-NAME, suggesting that VlvEC produced NO inhibits VIC activation. Withdrawal of l-NAME after 3, 5, and 7 days with restoration of VlvEC NO production for 2 additional days led to a partial reversal of VIC activation (∼25% decrease). A potential mechanism by which VlvEC produced NO reduced VIC activation was studied by inhibiting initial and mid-stage cGMP pathway molecules. Inhibition of soluble guanylyl cyclase (sGC) with ODQ or protein kinase G (PKG) with RBrcGMP or stimulation of Rho kinase (ROCK) with LPA, abolished VlvEC effects on VIC activation. This work contributes substantially to the understanding of the valve endothelium's role in preventing VIC functions associated with aortic valve stenosis initiation and progression.

PEG hydrogels

Valvular interstitial cells

Nitric oxide

α-Smooth muscle actin

Valvular endothelial cells

Details

Title: Subtitle: The role of valvular endothelial cell paracrine signaling and matrix elasticity on valvular interstitial cell activation
Creators: Sarah T Gould - Department of Chemical and Biological Engineering, The BioFrontiers Institute, Boulder, CO 80303, USA
Emily E Matherly - Department of Chemical and Biological Engineering, The BioFrontiers Institute, Boulder, CO 80303, USA
Jennifer N Smith - Department of Chemical and Biological Engineering, The BioFrontiers Institute, Boulder, CO 80303, USA
Donald D Heistad - Departments of Internal Medicine and Pharmacology, University of Iowa Health Care, Iowa City, IA 52242, USA
Kristi S Anseth - Department of Chemical and Biological Engineering, The BioFrontiers Institute, Boulder, CO 80303, USA
Resource Type: Journal article
Publication Details: Biomaterials, Vol.35(11), pp.3596-3606
DOI: 10.1016/j.biomaterials.2014.01.005
PMID: 24462357
PMCID: PMC4040249
NLM abbreviation: Biomaterials
ISSN: 0142-9612
eISSN: 1878-5905
Publisher: Elsevier Ltd
Grant note: name: National Institute of Health, award: NIH R01 HL089260, HL 62984; name: Howard Hughes Medical Institute (HHMI)
Language: English
Date published: 04/2014
Academic Unit: Cardiovascular Medicine; Neuroscience and Pharmacology; Internal Medicine
Record Identifier: 9984040240002771

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