Advanced

Pyk2 inhibition promotes contractile differentiation in arterial smooth muscle

Grossi, Mario LU ; Bhattachariya, Anirban LU ; Nordström, Ina LU ; Turczyńska, Karolina M. LU ; Svensson, Daniel LU ; Albinsson, Sebastian LU ; Nilsson, Bengt Olof LU and Hellstrand, Per LU (2017) In Journal of Cellular Physiology 232(11). p.3088-3102
Abstract

Modulation from contractile to synthetic phenotype of vascular smooth muscle cells is a central process in disorders involving compromised integrity of the vascular wall. Phenotype modulation has been shown to include transition from voltage-dependent toward voltage-independent regulation of the intracellular calcium level, and inhibition of non-voltage dependent calcium influx contributes to maintenance of the contractile phenotype. One possible mediator of calcium-dependent signaling is the FAK-family non-receptor protein kinase Pyk2, which is activated by a number of stimuli in a calcium-dependent manner. We used the Pyk2 inhibitor PF-4594755 and Pyk2 siRNA to investigate the role of Pyk2 in phenotype modulation in rat carotid artery... (More)

Modulation from contractile to synthetic phenotype of vascular smooth muscle cells is a central process in disorders involving compromised integrity of the vascular wall. Phenotype modulation has been shown to include transition from voltage-dependent toward voltage-independent regulation of the intracellular calcium level, and inhibition of non-voltage dependent calcium influx contributes to maintenance of the contractile phenotype. One possible mediator of calcium-dependent signaling is the FAK-family non-receptor protein kinase Pyk2, which is activated by a number of stimuli in a calcium-dependent manner. We used the Pyk2 inhibitor PF-4594755 and Pyk2 siRNA to investigate the role of Pyk2 in phenotype modulation in rat carotid artery smooth muscle cells and in cultured intact arteries. Pyk2 inhibition promoted the expression of smooth muscle markers at the mRNA and protein levels under stimulation by FBS or PDGF-BB and counteracted phenotype shift in cultured intact carotid arteries and balloon injury ex vivo. During long-term (24–96 hr) treatment with PF-4594755, smooth muscle markers increased before cell proliferation was inhibited, correlating with decreased KLF4 expression and differing from effects of MEK inhibition. The Pyk2 inhibitor reduced Orai1 and preserved SERCA2a expression in carotid artery segments in organ culture, and eliminated the inhibitory effect of PDGF stimulation on L-type calcium channel and large-conductance calcium-activated potassium channel expression in carotid cells. Basal intracellular calcium level, calcium wave activity, and store-operated calcium influx were reduced after Pyk2 inhibition of growth-stimulated cells. Pyk2 inhibition may provide an interesting approach for preserving vascular smooth muscle differentiation under pathophysiological conditions.

(Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
calcium, PF-459475, phenotype, SERCA, vascular remodeling
in
Journal of Cellular Physiology
volume
232
issue
11
pages
15 pages
publisher
John Wiley & Sons
external identifiers
  • scopus:85017340415
  • wos:000407020800019
ISSN
0021-9541
DOI
10.1002/jcp.25760
language
English
LU publication?
yes
id
eb471c54-d38e-4480-8c46-4392a5497dfe
date added to LUP
2017-11-22 12:28:08
date last changed
2018-01-16 13:26:16
@article{eb471c54-d38e-4480-8c46-4392a5497dfe,
  abstract     = {<p>Modulation from contractile to synthetic phenotype of vascular smooth muscle cells is a central process in disorders involving compromised integrity of the vascular wall. Phenotype modulation has been shown to include transition from voltage-dependent toward voltage-independent regulation of the intracellular calcium level, and inhibition of non-voltage dependent calcium influx contributes to maintenance of the contractile phenotype. One possible mediator of calcium-dependent signaling is the FAK-family non-receptor protein kinase Pyk2, which is activated by a number of stimuli in a calcium-dependent manner. We used the Pyk2 inhibitor PF-4594755 and Pyk2 siRNA to investigate the role of Pyk2 in phenotype modulation in rat carotid artery smooth muscle cells and in cultured intact arteries. Pyk2 inhibition promoted the expression of smooth muscle markers at the mRNA and protein levels under stimulation by FBS or PDGF-BB and counteracted phenotype shift in cultured intact carotid arteries and balloon injury ex vivo. During long-term (24–96 hr) treatment with PF-4594755, smooth muscle markers increased before cell proliferation was inhibited, correlating with decreased KLF4 expression and differing from effects of MEK inhibition. The Pyk2 inhibitor reduced Orai1 and preserved SERCA2a expression in carotid artery segments in organ culture, and eliminated the inhibitory effect of PDGF stimulation on L-type calcium channel and large-conductance calcium-activated potassium channel expression in carotid cells. Basal intracellular calcium level, calcium wave activity, and store-operated calcium influx were reduced after Pyk2 inhibition of growth-stimulated cells. Pyk2 inhibition may provide an interesting approach for preserving vascular smooth muscle differentiation under pathophysiological conditions.</p>},
  author       = {Grossi, Mario and Bhattachariya, Anirban and Nordström, Ina and Turczyńska, Karolina M. and Svensson, Daniel and Albinsson, Sebastian and Nilsson, Bengt Olof and Hellstrand, Per},
  issn         = {0021-9541},
  keyword      = {calcium,PF-459475,phenotype,SERCA,vascular remodeling},
  language     = {eng},
  month        = {11},
  number       = {11},
  pages        = {3088--3102},
  publisher    = {John Wiley & Sons},
  series       = {Journal of Cellular Physiology},
  title        = {Pyk2 inhibition promotes contractile differentiation in arterial smooth muscle},
  url          = {http://dx.doi.org/10.1002/jcp.25760},
  volume       = {232},
  year         = {2017},
}