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Mechanotransduction
Arun.V.
MSc.BMB
14368005
And its Role in Atherosclerosis
© Arun Viswanathan
What is
Mechanotransduction?
“The processes through
which cells sense and
respond to mechanical
stimuli by converting
them to biochemical
signals that elicit
specific cellular
responses.”
Defines this subject area as
© Arun Viswanathan
How
MT happens?
transduction of physical•
forces occur through
changes in protein
conformation
Protein folding favors the•
conformation that yields
the lowest free energy
physical forces that•
modify the energy
landscape will directly
alter protein folding.
©Mechanisms of Mechanotransduction
A. Wayne Orr, Brian P. Helmke, Brett R.
Blackman, Martin A. Schwartz
Change in confirmation
Change in folding
© Arun Viswanathan
“Force-induced effects on conformation of
protein is a general mechanism by which
enzymatic activity or protein interactions can
be modified to mediate signaling in MT.”
A unifying principle
© Arun Viswanathan
Stretch-sensitive channels Example
• Increasing tension within the
lipid bilayer from 10–12 to 20
dyn/cm increases channel
opening probability.
• open state occupies a greater
area in the bilayer, membrane
tension will result directly in
lower free energy.
Mechanisms of Mechanotransduction; A. Wayne Orr, Brian P.
Helmke, Brett R. Blackman, Martin A. Schwartz; Developmental Cell,
Volume 10, Issue 3, March 2006, Page 407 © Arun Viswanathan
Mechanosensistive Channel-L Example
(A) Structure of the MscL channel in the
open state viewed from the
extracellular side. It opens and
close like an iris of camera
(B) MscL is a homopentamer whose
subunits have two α-helical TM
domains, TM1 and TM2,
cytoplasmic N- and C-terminal
domains and a central periplasmic
domain. Side views of the
transmembrane domains TM1 and
TM2 of the open channel. The inset
shows the structure of the channel
monomer.
Open channel structure of MscL and the gating mechanism of mechanosensitive
channels, Eduardo Perozo, D. Marien Cortes, Pornthep Sompornpisut, Anna
Kloda & Boris Martinac; Nature 418, 942-948 (29 August 2002) |
doi:10.1038/nature00992; Received 4 April 2002 © Arun Viswanathan
Mechanosensistive Channel-L Example
Changes in the spectral line shape from
position Ile24 obtained by the EPR
spectroscopy were used to monitor the
influence of different bilayer tension
gradients produced by different lipid
environments on the conformation of
MscL:
• Symmetric phosphatidylcholine
(PC18; closed),
• Asymmetric
lysophosphatidylcholine (LPC;
open),
• Detergent solution (closed)
• Symmetric LPC (closed)
Note, narrowing of the spectral line
after addition of LPC to one monolayer
is characteristic of the open
channel.
Underlying the transduction of bilayer deformation forces during
mechanosensitive channel gating ;Eduardo Perozo, Anna Kloda2 D. Marien
Cortes & Boris Martinac; Nature Structural Biology 9, 696 - 703 (2002)
Published online: 12 August 2002; | doi:10.1038/nsb827 Physical principles © Arun Viswanathan
(1) phosphorylation &
activation of MAP
kinase signaling
pathways (denoted
by MEKK and JNK)
that lead to ERK1/2
phosphorylation,
(2) activation of PLC
leading to IP3
generation and
gating of intracellular
Ca2+ stores
(3) alterations in the
actin cytoskeleton
network.
Phosphorylated
ERK1/2 causes the
activation of the AP-
1 family of TF
Signaling : mechanical to
chemical signals
© Arun Viswanathan
Signaling : mechanical to
chemical signals
There is a common
mechanism for MT in
cells, regardless of the
cell type. Integrins,
interacting with their
matrix/environment,
mediate increases in
intracellular Ca2+ levels
and activate MAP kinase
cascades to cause
ERK1/2
phosphorylation.
Phosphorylated ERK1/2
causes the activation of
AP-1 family of TFs that
are necessary for the
pro-growth response. © Arun Viswanathan
(1) Glycocalix : mediate MT signalling in
response to fluid shear stress ECs
(2) Cell-cell junctional receptors
(3) cell-matrix focal adhesions allow the
cells to probe its environment.
(4) Force-induced unfolding of
extracellular matrix proteins
(fibronectin) : initiate MT signalling
outside the cell.
(5) Intracellular strain can induce
conformational changes in
cytoskeletal elements by changing
binding affinities to specific
molecules & activating signalling
pathways.
(6) nucleus has been proposed to act as
a mechanosensor. Intracellular
deformations could alter chromatin
conformation and modulate access
to TFs & TMs. (direct evidence for this
mechanism is still lacking)
(7) Compression of the intercellular
space can alter the effective
concentration of autocrine and
paracrine signalling molecules.
(8) changes in G-protein coupled
receptors, lipid fluidity, and even
mitochondrial activity have been
proposed as mechanosensors
Myriad ways of MT
short term effects :
Increases (or decreases) in intracellular
tension, adhesion, spreading or migration
long term effects :
Protein synthesis/secretion, structural
reorganization, proliferation, viability
mediated through multiple, overlapping &
crosstalking signalling pathways.
© Arun Viswanathan
Diseases related to MT
© Arun Viswanathan
Atherosclerosis
Area of bifurcation
of blood vessels are
prone to
atherosclerosis
© Arun Viswanathan
Forces acting on blood vessels
shear stress parallel (tangential to the endothelial cell surface) by blood flow and
the generations of normal stress (perpendicular to the endothelial cell surface) and
circumferential stretch due to the action of pressure.
Circumferential Stress
(Cyclic Stress or stretch)
Mechanotransduction and endothelial cell homeostasis: the wisdom of the cell; Shu Chien; American Journal of Physiology - Heart and Circulatory Physiology
Published 1 March 2007 Vol. 292 no. 3, H1209-H1224 DOI: 10.1152/ajpheart.01047.2006 © Arun Viswanathan
Disturbed flow at bifurcation
Contours of the wall shear stress (N/m2) magnitude at the main and D1-S1 bifurcations
of coronary segments flow divider (FD) and lateral walls (LW).
Wall shear stress oscillation and its gradient
in the normal left coronary artery tree
bifurcations; Soulis JV, Fytanidis DK,
Seralidou KV, Giannoglou GD; Hippokratia
2014, 18, 1: 12-16
© Arun Viswanathan
Disturbed flow at bifurcation
Monocyte Adhesion(+)
LDL permeability(+)
Monocyte Adhesion(-)
LDL permeability(-)
Mechanotransduction in vascular physiology and
atherogenesis; Cornelia Hahn & Martin A. Schwartz
Nature Reviews Molecular Cell Biology 10, 53-62 (January
2009); doi:10.1038/nrm2596 © Arun Viswanathan
MT in response to shear stress
Mechanotransduction and endothelial cell homeostasis: the
wisdom of the cell; Shu Chien; American Journal of Physiology
- Heart and Circulatory Physiology Published 1 March 2007
Vol. 292 no. 3, H1209-H1224 DOI:
10.1152/ajpheart.01047.2006 © Arun Viswanathan
MT in response to shear stress
• shear stress can activate a number of
mechanosensors . These include membrane
proteins such as
– RTK(e.g., VEGFR Flk-1)
– the integrins (αvβ3, α2β1, α5β1, and α6β1)
– G proteins and G protein-coupled receptors
– Ca2+ channel
– intercellular junction proteins
– Membrane lipids and membrane glycocalyx may also
play a role.
© Arun Viswanathan
Effects of laminar and disturbed flow on EC proliferation
Laminar Flow p53
GADD45
p21
P-Rb
Cell Cycle
Arrest
in G0 and
G1
Disturbed Flow p53
GADD45
p21
P-Rb
Cell Cycle
progression
© Arun Viswanathan
MT in response to stretch
Mechanotransduction and endothelial
cell homeostasis: the wisdom of the
cell; Shu Chien; American Journal of
Physiology - Heart and Circulatory
Physiology Published 1 March 2007
Vol. 292 no. 3, H1209-H1224 DOI:
10.1152/ajpheart.01047.2006
© Arun Viswanathan
Cell borders : Beta-catenin mAb
F-Actin : Rhodamine Phalloidin
Uniaxial stretch causes an orientation of the stress fibers in a direction perpendicular to that of
stretch, whereas biaxial stretch does not result in any specific orientation of the stress fibers
MT in response to stretch
Mechanotransduction and endothelial cell
homeostasis: the wisdom of the cell; Shu
Chien; American Journal of Physiology -
Heart and Circulatory Physiology Published
1 March 2007 Vol. 292 no. 3, H1209-H1224
DOI: 10.1152/ajpheart.01047.2006 © Arun Viswanathan
Stretch and signaling
Mechanotransduction and endothelial cell
homeostasis: the wisdom of the cell; Shu
Chien; American Journal of Physiology -
Heart and Circulatory Physiology Published
1 March 2007 Vol. 292 no. 3, H1209-H1224
DOI: 10.1152/ajpheart.01047.2006 © Arun Viswanathan
JNK1 activation
ECs to uniaxial stretch for 6 h,
which has led to a
perpendicular stress fiber
alignment and subsidence of
JNK activation and then change
the direction of stretch by 90°.
Thus the uniaxial stretch is now
applied in a direction parallel to
the oriented stress fibers. This
change in direction results in a
transient reactivation of JNK
when the stress fibers are not
yet realigned. After 6 h of
uniaxial stretch in this new
direction, however, the stress
fibers become again oriented
perpendicular to the new
direction of stretch, and the
JNK activity then subsides once
again
Mechanotransduction and endothelial cell
homeostasis: the wisdom of the cell; Shu Chien;
American Journal of Physiology - Heart and
Circulatory Physiology Published 1 March 2007
Vol. 292 no. 3, H1209-H1224 DOI:
10.1152/ajpheart.01047.2006 © Arun Viswanathan
JNK1 activation is associated with apoptosis in EC’s
• Lack of a clear stretch direction in branch
points would not induce the feedback
minimization of intracellular stress
• Result: sustained activation of JNK
• The blockade of JNK activity by using the
negative interfering mutant JNK(K-R) markedly
decreased the apoptosis induced by colchicine.
•Activation of JNK is associated with apoptosis*
*Sustained JNK activation induces endothelial apoptosis: studies with colchicine and shear stress; Ying-Li Hu, Song Li, John Y.-J. Shyy, Shu Chien
American Journal of Physiology - Heart and Circulatory Physiology Published 1 October 1999 Vol. 277 no. 4, H1593-H1599 DOI:
© Arun Viswanathan
Monocyte Chemotactic Protein-1
• expression of MCP-1 gene is modulated by the Ras-mitogen-
activated protein kinases (MAPKs) pathway.
• The activation of MAPKs entails the phosphorylation of a series of
serine-threonine protein kinases with Ras serving as an upstream
molecule
• ERK, JNK, and p38 as three key downstream molecules
• application of a steady shear stress (12 dyn/cm2) to ECs causes Ras
to become bound with GTP instead of GDP,
• followed by the activation of MAPKs and the MCP-1 expression.
• sustained laminar shear stress causes the downregulation of Ras (a
few seconds), MAPKs (on the order of an hour), and MCP-1 gene
expression, which decreases to below the preshear level by 5 h
• laminar shear stress has a short-term effect of upregulation of
MCP-1, it has a long-term effect of downregulation when its
application is sustained
© Arun Viswanathan
MCP-1
ECs in static culture respond to the applied shear flow by a transient MCP-1
activation, which then vanishes when the cells adapt to the long-term shear
stress. The induction of MCP-1 expression by oxidative stress has been shown to
be attenuated by pulsatile shear stress and augmented by reciprocating shear
stress
© Arun Viswanathan
KLK-2 gene Expression
• Krüppel-like factor (Klf)-2 belongs to the zinc
finger family of DNA-binding transcription
factors.
• Klf2 was shown to be a potent inhibitor of
cytokine-mediated induction of VCAM-1 and
E-selectin expression in endothelial cells
• Anti-proliferative and Anti-inflamatory
© Arun Viswanathan
KLK-2 gene Expression
Mechanotransduction and endothelial cell
homeostasis: the wisdom of the cell; Shu
Chien; American Journal of Physiology -
Heart and Circulatory Physiology Published
1 March 2007 Vol. 292 no. 3, H1209-H1224
DOI: 10.1152/ajpheart.01047.2006 © Arun Viswanathan
three pictures showing enlarged
views of regions 1, 2, and 3 in B.
The expression of KLF2 was high
and continuous on ECs of the
abdominal aorta (labeled 3) and
the medial aspect (labeled 2) of
the celiac branch, but virtually
absent on the lateral aspect
(labeled 1) of the branch. These
results are representative of three
independent experiments. In C,
the short filled arrows (in 2 and 3)
indicate the positive staining for
KLF2 protein, and the open arrow
(in 1) shows the absence of KLF2
protein in the endothelium.
KLK-2 gene Expression
Mechanotransduction and endothelial cell
homeostasis: the wisdom of the cell; Shu
Chien; American Journal of Physiology -
Heart and Circulatory Physiology Published
1 March 2007 Vol. 292 no. 3, H1209-H1224
DOI: 10.1152/ajpheart.01047.2006 © Arun Viswanathan
Lipid Metabolism in EC
•The application of laminar shear stress (12 dyn/cm2)
causes a transient activation of SREBP1
•Disturbed flow causes a sustained activation of
SREBP1
•Cause translocation of TF domain into the nucleus
•Blockade of β1-integrin with AIIB2 blocking-type MAb
or disruption of actin cytoskeleton with cytochalasin
D inhibits the shear-activation of SREBP1
•indicating that integrins and the actin cytoskeleton
play significant roles in the modulation of EC lipid
metabolism in response to shear stress
© Arun Viswanathan
After being sheared for
1 or 12 h, the cells were
fixed and
immunostained for
SREBP1. Whereas
disturbed flow induced
a sustained activation
SREBP1, as indicated by
its translocation into
the nuclei (B, lower
left), laminar flow
activated SREBP1 in a
transient manner, as
evidenced by the lack of
nuclear staining of
SREBP1 at 12 h (B,
lower right).
© Arun Viswanathan
Leaky endothelium
Mechanical
Factors
Cell Turnover
LDL
LDL
Ox-LDL
Blood
Vessel Wall
MCP-1
Low KLK-2
Macrophage
Foam Cell
Endothelial Cells
SMCs
© Arun Viswanathan
Complete signaling
Straight Part Branching Point
Flow Pattern Laminar Disturbed
EC turnover Low High
LDL Permeability Low High
JNK1 Transient/optimum High/stable
MCP-1 Expression Low High
Klk-2 Expression Optimum Low
SREBP1 Not activated Activated
Effects on atherosclerosis Anti-Atherosclerosis Atherogenic
Summary
© Arun Viswanathan
• Mechanotransduction and endothelial cell homeostasis: the wisdom of the cell; Shu
Chien; American Journal of Physiology - Heart and Circulatory Physiology Published 1
March 2007 Vol. 292 no. 3, H1209-H1224 DOI: 10.1152/ajpheart.01047.2006
• Mechanotransduction in vascular physiology and atherogenesis; Cornelia Hahn &
Martin A. Schwartz Nature Reviews Molecular Cell Biology 10, 53-62 (January 2009);
doi:10.1038/nrm2596
• Mechanisms of Mechanotransduction A. Wayne Orr, Brian P. Helmke, Brett R.
Blackman, Martin A. Schwartz
• Wall shear stress oscillation and its gradient in the normal left coronary artery tree
bifurcations; Soulis JV, Fytanidis DK, Seralidou KV, Giannoglou GD; Hippokratia 2014,
18, 1: 12-16
• Diana E. Jaalouk and Jan Lammerding; Mechanotransduction gone awry; Nat Rev
Mol Cell Biol. Author manuscript; available in PMC 2009 Jul 1. Published in final
edited form as: Nat Rev Mol Cell Biol. 2009 Jan; 10(1): 63–73.
doi: 10.1038/nrm2597
• Shear Stress Activation of SREBP1 in Endothelial Cells Is Mediated by Integrins; Yi Liu,
Benjamin P.-C. Chen, Min Lu, Yi Zhu, Michael B. Stemerman, Shu Chien, John Y.-J.
Shyy
References
© Arun Viswanathan

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Mechanotrasduction and its role in atherosclerosis

  • 1. Mechanotransduction Arun.V. MSc.BMB 14368005 And its Role in Atherosclerosis © Arun Viswanathan
  • 2. What is Mechanotransduction? “The processes through which cells sense and respond to mechanical stimuli by converting them to biochemical signals that elicit specific cellular responses.” Defines this subject area as © Arun Viswanathan
  • 3. How MT happens? transduction of physical• forces occur through changes in protein conformation Protein folding favors the• conformation that yields the lowest free energy physical forces that• modify the energy landscape will directly alter protein folding. ©Mechanisms of Mechanotransduction A. Wayne Orr, Brian P. Helmke, Brett R. Blackman, Martin A. Schwartz Change in confirmation Change in folding © Arun Viswanathan
  • 4. “Force-induced effects on conformation of protein is a general mechanism by which enzymatic activity or protein interactions can be modified to mediate signaling in MT.” A unifying principle © Arun Viswanathan
  • 5. Stretch-sensitive channels Example • Increasing tension within the lipid bilayer from 10–12 to 20 dyn/cm increases channel opening probability. • open state occupies a greater area in the bilayer, membrane tension will result directly in lower free energy. Mechanisms of Mechanotransduction; A. Wayne Orr, Brian P. Helmke, Brett R. Blackman, Martin A. Schwartz; Developmental Cell, Volume 10, Issue 3, March 2006, Page 407 © Arun Viswanathan
  • 6. Mechanosensistive Channel-L Example (A) Structure of the MscL channel in the open state viewed from the extracellular side. It opens and close like an iris of camera (B) MscL is a homopentamer whose subunits have two α-helical TM domains, TM1 and TM2, cytoplasmic N- and C-terminal domains and a central periplasmic domain. Side views of the transmembrane domains TM1 and TM2 of the open channel. The inset shows the structure of the channel monomer. Open channel structure of MscL and the gating mechanism of mechanosensitive channels, Eduardo Perozo, D. Marien Cortes, Pornthep Sompornpisut, Anna Kloda & Boris Martinac; Nature 418, 942-948 (29 August 2002) | doi:10.1038/nature00992; Received 4 April 2002 © Arun Viswanathan
  • 7. Mechanosensistive Channel-L Example Changes in the spectral line shape from position Ile24 obtained by the EPR spectroscopy were used to monitor the influence of different bilayer tension gradients produced by different lipid environments on the conformation of MscL: • Symmetric phosphatidylcholine (PC18; closed), • Asymmetric lysophosphatidylcholine (LPC; open), • Detergent solution (closed) • Symmetric LPC (closed) Note, narrowing of the spectral line after addition of LPC to one monolayer is characteristic of the open channel. Underlying the transduction of bilayer deformation forces during mechanosensitive channel gating ;Eduardo Perozo, Anna Kloda2 D. Marien Cortes & Boris Martinac; Nature Structural Biology 9, 696 - 703 (2002) Published online: 12 August 2002; | doi:10.1038/nsb827 Physical principles © Arun Viswanathan
  • 8. (1) phosphorylation & activation of MAP kinase signaling pathways (denoted by MEKK and JNK) that lead to ERK1/2 phosphorylation, (2) activation of PLC leading to IP3 generation and gating of intracellular Ca2+ stores (3) alterations in the actin cytoskeleton network. Phosphorylated ERK1/2 causes the activation of the AP- 1 family of TF Signaling : mechanical to chemical signals © Arun Viswanathan
  • 9. Signaling : mechanical to chemical signals There is a common mechanism for MT in cells, regardless of the cell type. Integrins, interacting with their matrix/environment, mediate increases in intracellular Ca2+ levels and activate MAP kinase cascades to cause ERK1/2 phosphorylation. Phosphorylated ERK1/2 causes the activation of AP-1 family of TFs that are necessary for the pro-growth response. © Arun Viswanathan
  • 10. (1) Glycocalix : mediate MT signalling in response to fluid shear stress ECs (2) Cell-cell junctional receptors (3) cell-matrix focal adhesions allow the cells to probe its environment. (4) Force-induced unfolding of extracellular matrix proteins (fibronectin) : initiate MT signalling outside the cell. (5) Intracellular strain can induce conformational changes in cytoskeletal elements by changing binding affinities to specific molecules & activating signalling pathways. (6) nucleus has been proposed to act as a mechanosensor. Intracellular deformations could alter chromatin conformation and modulate access to TFs & TMs. (direct evidence for this mechanism is still lacking) (7) Compression of the intercellular space can alter the effective concentration of autocrine and paracrine signalling molecules. (8) changes in G-protein coupled receptors, lipid fluidity, and even mitochondrial activity have been proposed as mechanosensors Myriad ways of MT short term effects : Increases (or decreases) in intracellular tension, adhesion, spreading or migration long term effects : Protein synthesis/secretion, structural reorganization, proliferation, viability mediated through multiple, overlapping & crosstalking signalling pathways. © Arun Viswanathan
  • 11. Diseases related to MT © Arun Viswanathan
  • 12. Atherosclerosis Area of bifurcation of blood vessels are prone to atherosclerosis © Arun Viswanathan
  • 13. Forces acting on blood vessels shear stress parallel (tangential to the endothelial cell surface) by blood flow and the generations of normal stress (perpendicular to the endothelial cell surface) and circumferential stretch due to the action of pressure. Circumferential Stress (Cyclic Stress or stretch) Mechanotransduction and endothelial cell homeostasis: the wisdom of the cell; Shu Chien; American Journal of Physiology - Heart and Circulatory Physiology Published 1 March 2007 Vol. 292 no. 3, H1209-H1224 DOI: 10.1152/ajpheart.01047.2006 © Arun Viswanathan
  • 14. Disturbed flow at bifurcation Contours of the wall shear stress (N/m2) magnitude at the main and D1-S1 bifurcations of coronary segments flow divider (FD) and lateral walls (LW). Wall shear stress oscillation and its gradient in the normal left coronary artery tree bifurcations; Soulis JV, Fytanidis DK, Seralidou KV, Giannoglou GD; Hippokratia 2014, 18, 1: 12-16 © Arun Viswanathan
  • 15. Disturbed flow at bifurcation Monocyte Adhesion(+) LDL permeability(+) Monocyte Adhesion(-) LDL permeability(-) Mechanotransduction in vascular physiology and atherogenesis; Cornelia Hahn & Martin A. Schwartz Nature Reviews Molecular Cell Biology 10, 53-62 (January 2009); doi:10.1038/nrm2596 © Arun Viswanathan
  • 16. MT in response to shear stress Mechanotransduction and endothelial cell homeostasis: the wisdom of the cell; Shu Chien; American Journal of Physiology - Heart and Circulatory Physiology Published 1 March 2007 Vol. 292 no. 3, H1209-H1224 DOI: 10.1152/ajpheart.01047.2006 © Arun Viswanathan
  • 17. MT in response to shear stress • shear stress can activate a number of mechanosensors . These include membrane proteins such as – RTK(e.g., VEGFR Flk-1) – the integrins (αvβ3, α2β1, α5β1, and α6β1) – G proteins and G protein-coupled receptors – Ca2+ channel – intercellular junction proteins – Membrane lipids and membrane glycocalyx may also play a role. © Arun Viswanathan
  • 18. Effects of laminar and disturbed flow on EC proliferation Laminar Flow p53 GADD45 p21 P-Rb Cell Cycle Arrest in G0 and G1 Disturbed Flow p53 GADD45 p21 P-Rb Cell Cycle progression © Arun Viswanathan
  • 19. MT in response to stretch Mechanotransduction and endothelial cell homeostasis: the wisdom of the cell; Shu Chien; American Journal of Physiology - Heart and Circulatory Physiology Published 1 March 2007 Vol. 292 no. 3, H1209-H1224 DOI: 10.1152/ajpheart.01047.2006 © Arun Viswanathan
  • 20. Cell borders : Beta-catenin mAb F-Actin : Rhodamine Phalloidin Uniaxial stretch causes an orientation of the stress fibers in a direction perpendicular to that of stretch, whereas biaxial stretch does not result in any specific orientation of the stress fibers MT in response to stretch Mechanotransduction and endothelial cell homeostasis: the wisdom of the cell; Shu Chien; American Journal of Physiology - Heart and Circulatory Physiology Published 1 March 2007 Vol. 292 no. 3, H1209-H1224 DOI: 10.1152/ajpheart.01047.2006 © Arun Viswanathan
  • 21. Stretch and signaling Mechanotransduction and endothelial cell homeostasis: the wisdom of the cell; Shu Chien; American Journal of Physiology - Heart and Circulatory Physiology Published 1 March 2007 Vol. 292 no. 3, H1209-H1224 DOI: 10.1152/ajpheart.01047.2006 © Arun Viswanathan
  • 22. JNK1 activation ECs to uniaxial stretch for 6 h, which has led to a perpendicular stress fiber alignment and subsidence of JNK activation and then change the direction of stretch by 90°. Thus the uniaxial stretch is now applied in a direction parallel to the oriented stress fibers. This change in direction results in a transient reactivation of JNK when the stress fibers are not yet realigned. After 6 h of uniaxial stretch in this new direction, however, the stress fibers become again oriented perpendicular to the new direction of stretch, and the JNK activity then subsides once again Mechanotransduction and endothelial cell homeostasis: the wisdom of the cell; Shu Chien; American Journal of Physiology - Heart and Circulatory Physiology Published 1 March 2007 Vol. 292 no. 3, H1209-H1224 DOI: 10.1152/ajpheart.01047.2006 © Arun Viswanathan
  • 23. JNK1 activation is associated with apoptosis in EC’s • Lack of a clear stretch direction in branch points would not induce the feedback minimization of intracellular stress • Result: sustained activation of JNK • The blockade of JNK activity by using the negative interfering mutant JNK(K-R) markedly decreased the apoptosis induced by colchicine. •Activation of JNK is associated with apoptosis* *Sustained JNK activation induces endothelial apoptosis: studies with colchicine and shear stress; Ying-Li Hu, Song Li, John Y.-J. Shyy, Shu Chien American Journal of Physiology - Heart and Circulatory Physiology Published 1 October 1999 Vol. 277 no. 4, H1593-H1599 DOI: © Arun Viswanathan
  • 24. Monocyte Chemotactic Protein-1 • expression of MCP-1 gene is modulated by the Ras-mitogen- activated protein kinases (MAPKs) pathway. • The activation of MAPKs entails the phosphorylation of a series of serine-threonine protein kinases with Ras serving as an upstream molecule • ERK, JNK, and p38 as three key downstream molecules • application of a steady shear stress (12 dyn/cm2) to ECs causes Ras to become bound with GTP instead of GDP, • followed by the activation of MAPKs and the MCP-1 expression. • sustained laminar shear stress causes the downregulation of Ras (a few seconds), MAPKs (on the order of an hour), and MCP-1 gene expression, which decreases to below the preshear level by 5 h • laminar shear stress has a short-term effect of upregulation of MCP-1, it has a long-term effect of downregulation when its application is sustained © Arun Viswanathan
  • 25. MCP-1 ECs in static culture respond to the applied shear flow by a transient MCP-1 activation, which then vanishes when the cells adapt to the long-term shear stress. The induction of MCP-1 expression by oxidative stress has been shown to be attenuated by pulsatile shear stress and augmented by reciprocating shear stress © Arun Viswanathan
  • 26. KLK-2 gene Expression • Krüppel-like factor (Klf)-2 belongs to the zinc finger family of DNA-binding transcription factors. • Klf2 was shown to be a potent inhibitor of cytokine-mediated induction of VCAM-1 and E-selectin expression in endothelial cells • Anti-proliferative and Anti-inflamatory © Arun Viswanathan
  • 27. KLK-2 gene Expression Mechanotransduction and endothelial cell homeostasis: the wisdom of the cell; Shu Chien; American Journal of Physiology - Heart and Circulatory Physiology Published 1 March 2007 Vol. 292 no. 3, H1209-H1224 DOI: 10.1152/ajpheart.01047.2006 © Arun Viswanathan
  • 28. three pictures showing enlarged views of regions 1, 2, and 3 in B. The expression of KLF2 was high and continuous on ECs of the abdominal aorta (labeled 3) and the medial aspect (labeled 2) of the celiac branch, but virtually absent on the lateral aspect (labeled 1) of the branch. These results are representative of three independent experiments. In C, the short filled arrows (in 2 and 3) indicate the positive staining for KLF2 protein, and the open arrow (in 1) shows the absence of KLF2 protein in the endothelium. KLK-2 gene Expression Mechanotransduction and endothelial cell homeostasis: the wisdom of the cell; Shu Chien; American Journal of Physiology - Heart and Circulatory Physiology Published 1 March 2007 Vol. 292 no. 3, H1209-H1224 DOI: 10.1152/ajpheart.01047.2006 © Arun Viswanathan
  • 29. Lipid Metabolism in EC •The application of laminar shear stress (12 dyn/cm2) causes a transient activation of SREBP1 •Disturbed flow causes a sustained activation of SREBP1 •Cause translocation of TF domain into the nucleus •Blockade of β1-integrin with AIIB2 blocking-type MAb or disruption of actin cytoskeleton with cytochalasin D inhibits the shear-activation of SREBP1 •indicating that integrins and the actin cytoskeleton play significant roles in the modulation of EC lipid metabolism in response to shear stress © Arun Viswanathan
  • 30. After being sheared for 1 or 12 h, the cells were fixed and immunostained for SREBP1. Whereas disturbed flow induced a sustained activation SREBP1, as indicated by its translocation into the nuclei (B, lower left), laminar flow activated SREBP1 in a transient manner, as evidenced by the lack of nuclear staining of SREBP1 at 12 h (B, lower right). © Arun Viswanathan
  • 31. Leaky endothelium Mechanical Factors Cell Turnover LDL LDL Ox-LDL Blood Vessel Wall MCP-1 Low KLK-2 Macrophage Foam Cell Endothelial Cells SMCs © Arun Viswanathan
  • 32. Complete signaling Straight Part Branching Point Flow Pattern Laminar Disturbed EC turnover Low High LDL Permeability Low High JNK1 Transient/optimum High/stable MCP-1 Expression Low High Klk-2 Expression Optimum Low SREBP1 Not activated Activated Effects on atherosclerosis Anti-Atherosclerosis Atherogenic Summary © Arun Viswanathan
  • 33. • Mechanotransduction and endothelial cell homeostasis: the wisdom of the cell; Shu Chien; American Journal of Physiology - Heart and Circulatory Physiology Published 1 March 2007 Vol. 292 no. 3, H1209-H1224 DOI: 10.1152/ajpheart.01047.2006 • Mechanotransduction in vascular physiology and atherogenesis; Cornelia Hahn & Martin A. Schwartz Nature Reviews Molecular Cell Biology 10, 53-62 (January 2009); doi:10.1038/nrm2596 • Mechanisms of Mechanotransduction A. Wayne Orr, Brian P. Helmke, Brett R. Blackman, Martin A. Schwartz • Wall shear stress oscillation and its gradient in the normal left coronary artery tree bifurcations; Soulis JV, Fytanidis DK, Seralidou KV, Giannoglou GD; Hippokratia 2014, 18, 1: 12-16 • Diana E. Jaalouk and Jan Lammerding; Mechanotransduction gone awry; Nat Rev Mol Cell Biol. Author manuscript; available in PMC 2009 Jul 1. Published in final edited form as: Nat Rev Mol Cell Biol. 2009 Jan; 10(1): 63–73. doi: 10.1038/nrm2597 • Shear Stress Activation of SREBP1 in Endothelial Cells Is Mediated by Integrins; Yi Liu, Benjamin P.-C. Chen, Min Lu, Yi Zhu, Michael B. Stemerman, Shu Chien, John Y.-J. Shyy References © Arun Viswanathan

Editor's Notes

  1. Schematic diagram showing the action of shear stress on potential sensors in endothelial cells, including receptor tyrosine kinases (RTK), G protein-coupled receptor (GPCR), ion channels, junction proteins, and integrins, as well as membrane lipids and glycocalyx. These mechanosensors act through adaptor molecules (represented by the two dotted circles) to activate upstream signaling molecules such as Ras, which then activates the mitogen-activated protein (MAP) kinase pathways, including ERK and JNK, and then the transcription factors (e.g., activator protein-1, AP-1) for gene expression (e.g., monocyte chemotactic protein-1, MCP-1). Arrows to the left of ERK and JNK are used to represent the phosphorylation cascade that involves the sequential phosphorylation of protein kinases one after the other. Various mechanotransduction pathways are used to modulate the expression of different genes. Also shown are the small GTPase Rho and its downstream molecules Rho kinase (ROCK) and mDia, which are stimulatory to actin. It is also possible for mechanical signals to be perceived by the cytoskeleton, including actin, to modulate gene expression. Shown are the interactions (direct or indirect) between JNK and actin. There are many signaling pathways that are not shown in this figure. This diagram illustrates that mechanotransduction involves the interplay among many mechanosensors, signaling molecules, and genes, all of which form complex networks to modulate EC structure and function.