PMID- 22307683
OWN - NLM
STAT- MEDLINE
DCOM- 20130711
LR  - 20211021
IS  - 1617-7940 (Electronic)
IS  - 1617-7959 (Print)
IS  - 1617-7940 (Linking)
VI  - 12
IP  - 1
DP  - 2013 Jan
TI  - Calcific nodule morphogenesis by heart valve interstitial cells is strain 
      dependent.
PG  - 5-17
LID - 10.1007/s10237-012-0377-8 [doi]
AB  - Calcific aortic valve disease (CAVD) results in impaired function through the 
      inability of valves to fully open and close, but the causes of this pathology are 
      unknown. Stiffening of the aorta is associated with CAVD and results in exposing 
      the aortic valves to greater mechanical strain. Transforming growth factor beta1 
      (TGF-beta1) is enriched in diseased valves and has been shown to combine with strain 
      to synergistically alter aortic valve interstitial cell (AVIC) phenotypes. 
      Therefore, we investigated the role of strain and TGF-beta1 on the calcification of 
      AVICs. Following TGF-beta1 pretreatment, strain induced intact monolayers to 
      aggregate and calcify. Using a wound assay, we confirmed that TGF-beta1 increases 
      tension in the monolayer in parallel with alpha-smooth muscle actin (alphaSMA) 
      expression. Continual exposure to strain accelerates aggregates to calcify into 
      mature nodules that contain a necrotic core surrounded by an apoptotic ring. This 
      phenotype appears to be mediated by strain inhibition of AVIC migration after the 
      initial formation of aggregates. To better interpret the extent to which 
      externally applied strain physically impacts this process, we modified the 
      classical Lame solution, derived using principles from linear elasticity, to 
      reveal strain magnification as a novel feature occurring in a mechanical 
      environment that supports nodule formation. These results indicate that strain 
      can impact multiple points of nodule formation: by modifying tension in the 
      monolayer, remodeling cell contacts, migration, apoptosis, and mineralization. 
      Therefore, strain-induced nodule formation provides new directions for developing 
      strategies to address CAVD.
FAU - Fisher, Charles I
AU  - Fisher CI
AD  - Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 
      37232-0493, USA.
FAU - Chen, Joseph
AU  - Chen J
FAU - Merryman, W David
AU  - Merryman WD
LA  - eng
GR  - K25 HL094707/HL/NHLBI NIH HHS/United States
GR  - K25 HL094707-04/HL/NHLBI NIH HHS/United States
GR  - K25 HL094707-05/HL/NHLBI NIH HHS/United States
GR  - HL094707/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20120204
PL  - Germany
TA  - Biomech Model Mechanobiol
JT  - Biomechanics and modeling in mechanobiology
JID - 101135325
RN  - 0 (Transforming Growth Factor beta1)
RN  - Aortic Valve, Calcification of
SB  - IM
MH  - Animals
MH  - Aortic Diseases/complications/*physiopathology
MH  - Aortic Valve/pathology/*physiopathology
MH  - Aortic Valve Stenosis/*physiopathology
MH  - Calcinosis/*physiopathology
MH  - Computer Simulation
MH  - Elastic Modulus
MH  - In Vitro Techniques
MH  - *Mechanotransduction, Cellular
MH  - *Models, Cardiovascular
MH  - *Morphogenesis
MH  - Stress, Mechanical
MH  - Swine
MH  - Tensile Strength
MH  - Transforming Growth Factor beta1/*metabolism
PMC - PMC3375394
MID - NIHMS362122
EDAT- 2012/02/07 06:00
MHDA- 2013/07/13 06:00
PMCR- 2014/01/01
CRDT- 2012/02/07 06:00
PHST- 2011/09/12 00:00 [received]
PHST- 2012/01/18 00:00 [accepted]
PHST- 2012/02/07 06:00 [entrez]
PHST- 2012/02/07 06:00 [pubmed]
PHST- 2013/07/13 06:00 [medline]
PHST- 2014/01/01 00:00 [pmc-release]
AID - 10.1007/s10237-012-0377-8 [doi]
PST - ppublish
SO  - Biomech Model Mechanobiol. 2013 Jan;12(1):5-17. doi: 10.1007/s10237-012-0377-8. 
      Epub 2012 Feb 4.