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Regulation of the myogenic response and stretch-induced calcium signaling in the vascular wall: Novel insights into the role of microRNAs and protein tyrosine kinase 2

Bhattachariya, Anirban LU (2014) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2014:101.
Abstract
Intraluminal pressure has a significant impact on vascular adaptability, phenotype and regulation of blood flow and

pressure. On one hand, increased pressure/stretch for a prolonged time can cause structural changes in vessel wall; on

the other hand, lack of pressure/stretch can promote a phenotype shift. This thesis investigates novel roles of

microRNAs and protein tyrosine kinase 2 in pressure/stretch-induced signaling mechanisms in the vascular wall.

Using two different knockout mouse models, we uncovered a novel role of microRNAs in the pressure-induced

myogenic response. We demonstrated that global deletion of smooth muscle-specific microRNAs causes a loss of

pressure-induced... (More)
Intraluminal pressure has a significant impact on vascular adaptability, phenotype and regulation of blood flow and

pressure. On one hand, increased pressure/stretch for a prolonged time can cause structural changes in vessel wall; on

the other hand, lack of pressure/stretch can promote a phenotype shift. This thesis investigates novel roles of

microRNAs and protein tyrosine kinase 2 in pressure/stretch-induced signaling mechanisms in the vascular wall.

Using two different knockout mouse models, we uncovered a novel role of microRNAs in the pressure-induced

myogenic response. We demonstrated that global deletion of smooth muscle-specific microRNAs causes a loss of

pressure-induced contraction and that this likely involves diminished calcium influx due to reduced stretch-induced

activation of the PI3K/Akt pathway. Similarly, global deletion of the smooth muscle enriched miRNA-143/145 also

depleted myogenic responses but this effect could be due to several combined factors including loss of calcium influx

and decreased expression of myosin light chain kinase. Furthermore portal veins of miRNA-143/145 KO mice exhibit

lack of stretch-induced contractile differentiation, which may in part be due to a reduced expression of L-type calcium

channels caused by an increased expression of the transcriptional repressor DREAM. Using a novel small molecule

inhibitor of PYK2, we demonstrated that PYK2 could distinguish between non-voltage and voltage-dependent calcium

pools to initiate signal transduction in the smooth muscle of portal vein. Inhibition of PYK2 can reduce phenotype

modulation and apoptosis in balloon injured carotid arteries.

In conclusion, we have established an indispensable role of microRNAs in the presssure-induced myogenic response

and maintainance of stretch-induced conctractile differentiation. Morover we have established that PYK2 is involved in

stretch-induced calcium handling in spontaneously active portal vein and in phenotypic shift of smooth muscle cells

following vascular injury. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Professor Walsh, Michael, Faculty of Medicine, University of Calgary, Canada
organization
publishing date
type
Thesis
publication status
published
subject
keywords
portal vein, resistance artery, myogenic tone, PYK2, calcium, microRNA
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2014:101
pages
89 pages
publisher
Vascular Physiology, Lund University
defense location
Rune Grubb-salen, BMC, Sölvegatan 19, Lund.
defense date
2014-09-26 09:00
ISSN
1652-8220
ISBN
978-91-7619-030-2
language
English
LU publication?
yes
id
bbf5cca6-b2f1-47c1-9f02-e261d619ce51 (old id 4619000)
date added to LUP
2014-09-09 10:01:54
date last changed
2016-09-19 08:44:45
@phdthesis{bbf5cca6-b2f1-47c1-9f02-e261d619ce51,
  abstract     = {Intraluminal pressure has a significant impact on vascular adaptability, phenotype and regulation of blood flow and<br/><br>
pressure. On one hand, increased pressure/stretch for a prolonged time can cause structural changes in vessel wall; on<br/><br>
the other hand, lack of pressure/stretch can promote a phenotype shift. This thesis investigates novel roles of<br/><br>
microRNAs and protein tyrosine kinase 2 in pressure/stretch-induced signaling mechanisms in the vascular wall.<br/><br>
Using two different knockout mouse models, we uncovered a novel role of microRNAs in the pressure-induced<br/><br>
myogenic response. We demonstrated that global deletion of smooth muscle-specific microRNAs causes a loss of<br/><br>
pressure-induced contraction and that this likely involves diminished calcium influx due to reduced stretch-induced<br/><br>
activation of the PI3K/Akt pathway. Similarly, global deletion of the smooth muscle enriched miRNA-143/145 also<br/><br>
depleted myogenic responses but this effect could be due to several combined factors including loss of calcium influx<br/><br>
and decreased expression of myosin light chain kinase. Furthermore portal veins of miRNA-143/145 KO mice exhibit<br/><br>
lack of stretch-induced contractile differentiation, which may in part be due to a reduced expression of L-type calcium<br/><br>
channels caused by an increased expression of the transcriptional repressor DREAM. Using a novel small molecule<br/><br>
inhibitor of PYK2, we demonstrated that PYK2 could distinguish between non-voltage and voltage-dependent calcium<br/><br>
pools to initiate signal transduction in the smooth muscle of portal vein. Inhibition of PYK2 can reduce phenotype<br/><br>
modulation and apoptosis in balloon injured carotid arteries.<br/><br>
In conclusion, we have established an indispensable role of microRNAs in the presssure-induced myogenic response<br/><br>
and maintainance of stretch-induced conctractile differentiation. Morover we have established that PYK2 is involved in<br/><br>
stretch-induced calcium handling in spontaneously active portal vein and in phenotypic shift of smooth muscle cells<br/><br>
following vascular injury.},
  author       = {Bhattachariya, Anirban},
  isbn         = {978-91-7619-030-2},
  issn         = {1652-8220},
  keyword      = {portal vein,resistance artery,myogenic tone,PYK2,calcium,microRNA},
  language     = {eng},
  pages        = {89},
  publisher    = {Vascular Physiology, Lund University},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {Regulation of the myogenic response and stretch-induced calcium signaling in the vascular wall: Novel insights into the role of microRNAs and protein tyrosine kinase 2},
  volume       = {2014:101},
  year         = {2014},
}