PMID- 33922850
OWN - NLM
STAT- MEDLINE
DCOM- 20211108
LR  - 20220821
IS  - 2073-4409 (Electronic)
IS  - 2073-4409 (Linking)
VI  - 10
IP  - 5
DP  - 2021 Apr 23
TI  - Substrate Stiffness and Stretch Regulate Profibrotic Mechanosignaling in 
      Pulmonary Arterial Adventitial Fibroblasts.
LID - 10.3390/cells10051000 [doi]
LID - 1000
AB  - Pulmonary arterial adventitial fibroblasts (PAAFs) are important regulators of 
      fibrotic vascular remodeling during the progression of pulmonary arterial 
      hypertension (PAH), a disease that currently has no effective anti-fibrotic 
      treatments. We conducted in-vitro experiments in PAAFs cultured on hydrogels 
      attached to custom-made equibiaxial stretchers at 10% stretch and substrate 
      stiffnesses representing the mechanical conditions of mild and severe stages of 
      PAH. The expression of collagens alpha(1)I and alpha(1)III and elastin messenger RNAs 
      (Col1a1, Col3a1, Eln) were upregulated by increased stretch and substrate 
      stiffness, while lysyl oxidase-like 1 and alpha-smooth muscle actin messenger RNAs 
      (Loxl1, Acta2) were only significantly upregulated when the cells were grown on 
      matrices with an elevated stiffness representative of mild PAH but not on a 
      stiffness representative of severe PAH. Fibronectin messenger RNA (Fn1) levels 
      were significantly induced by increased substrate stiffness and transiently 
      upregulated by stretch at 4 h, but was not significantly altered by stretch at 24 
      h. We modified our published computational network model of the signaling 
      pathways that regulate profibrotic gene expression in PAAFs to allow for 
      differential regulation of mechanically-sensitive nodes by stretch and stiffness. 
      When the model was modified so that stiffness activated integrin beta(3), the 
      Macrophage Stimulating 1 or 2 (MST1\2) kinases, angiotensin II (Ang II), 
      transforming growth factor-beta (TGF-beta), and syndecan-4, and stretch-regulated 
      integrin beta(3), MST1\2, Ang II, and the transient receptor potential (TRP) 
      channel, the model correctly predicted the upregulation of all six genes by 
      increased stiffness and the observed responses to stretch in five out of six 
      genes, although it could not replicate the non-monotonic effects of stiffness on 
      Loxl1 and Acta2 expression. Blocking Ang II Receptor Type 1 (AT(1)R) with 
      losartan in-vitro uncovered an interaction between the effects of stretch and 
      stiffness and angiotensin-independent activation of Fn1 expression by stretch in 
      PAAFs grown on 3-kPa matrices. This novel combination of in-vitro and in-silico 
      models of PAAF profibrotic cell signaling in response to altered mechanical 
      conditions may help identify regulators of vascular adventitial remodeling due to 
      changes in stretch and matrix stiffness that occur during the progression of PAH 
      in-vivo.
FAU - Wang, Ariel
AU  - Wang A
AD  - Department of Bioengineering, University of California San Diego, La Jolla, CA 
      92093-0412, USA.
FAU - Cao, Shulin
AU  - Cao S
AD  - Department of Bioengineering, University of California San Diego, La Jolla, CA 
      92093-0412, USA.
FAU - Stowe, Jennifer C
AU  - Stowe JC
AD  - Department of Bioengineering, University of California San Diego, La Jolla, CA 
      92093-0412, USA.
FAU - Valdez-Jasso, Daniela
AU  - Valdez-Jasso D
AD  - Department of Bioengineering, University of California San Diego, La Jolla, CA 
      92093-0412, USA.
LA  - eng
GR  - 16SDG29670010/American Heart Association/
GR  - 1R25HL145817-01/HL/NHLBI NIH HHS/United States
GR  - 1T32HL105373/HL/NHLBI NIH HHS/United States
GR  - 1R01HL137100/HL/NHLBI NIH HHS/United States
GR  - R01 HL155945/HL/NHLBI NIH HHS/United States
GR  - R25 HL145817/HL/NHLBI NIH HHS/United States
GR  - S10 OD010417/OD/NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20210423
PL  - Switzerland
TA  - Cells
JT  - Cells
JID - 101600052
SB  - IM
MH  - Animals
MH  - Fibroblasts/metabolism/*pathology
MH  - Gene Expression Regulation
MH  - Hypertension, Pulmonary/metabolism/*pathology
MH  - Male
MH  - *Mechanotransduction, Cellular
MH  - Pulmonary Artery/metabolism/*pathology
MH  - Pulmonary Circulation
MH  - Pulmonary Fibrosis/metabolism/*pathology
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - *Stress, Mechanical
MH  - *Vascular Stiffness
PMC - PMC8146344
OTO - NOTNLM
OT  - computational modeling
OT  - fibroblasts
OT  - pulmonary arterial hypertension
OT  - stiffness
OT  - stretch
COIS- The authors declare no conflict of interest.
EDAT- 2021/05/01 06:00
MHDA- 2021/11/09 06:00
PMCR- 2021/04/23
CRDT- 2021/04/30 01:23
PHST- 2021/01/29 00:00 [received]
PHST- 2021/04/13 00:00 [revised]
PHST- 2021/04/21 00:00 [accepted]
PHST- 2021/04/30 01:23 [entrez]
PHST- 2021/05/01 06:00 [pubmed]
PHST- 2021/11/09 06:00 [medline]
PHST- 2021/04/23 00:00 [pmc-release]
AID - cells10051000 [pii]
AID - cells-10-01000 [pii]
AID - 10.3390/cells10051000 [doi]
PST - epublish
SO  - Cells. 2021 Apr 23;10(5):1000. doi: 10.3390/cells10051000.