Biomechanical Stress-initiated Vascular Remodeling and Signal Transduction in Smooth Muscle Cells
Department of Histology & Embryology
School of Basic Medical Sciences
Zhongshan University
GUANGZHOU, P.R.CHINA
Chaohong Li
李 朝 红
中山大学基础医学院组胚教研室
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Sympathetic nervous system
Vascular
remodeling
(arteriosclerosis)
Heart
remodeling
(heart failure)
Main Causes
to Mortality and Morbidity
Hypertension
Biomechanical stresses
Renin-angiotensin system
HYPOTHESIS-DRIVEN WORKING MODEL
Biomechanical Stress
Stretch stress: created by blood pressure
Shear stress: created by fluid flow across
INTRODUCTION
Normal mechanical stress
is essential for normal development, differentiation, and phenotype maintenance.
Hypertension-initiated abnormal mechanical stress
induces vascular remodeling
INTRODUCTION
1. How do the cells sense and transduce the extracellular mechanical stimuli into intracellular biochemical signals leading to cardiovascular remodeling?
Questions ?
2. Are there mechanoreceptors in cell membranes?
HYPOTHESIS-DRIVEN WORKING MODEL
Animal models of gene manipulating
(Gene knockout)
---PKCdelta-/-, G protein gamma 11-/-, p53-/-, ApoE-/- mice---
Mechanical stress models
(in vivo and in vitro)
Functional consequences
EXPERIMENTAL DESIGN
Molecular mechanisms of biomechanical stress-initiated remodeling of
---Vessels
---Heart
Vessels
in vitro: Signaling in VSMCS (Gene knockout mouse vascular smooth muscle cells)
(Receptors, G proteins, MAPKs, PKC etc)
MECHANICAL STRESS MODELS
in vivo: Mouse venous bypass graft arteriosclerosis
MECHANICAL STRESS MODELS
RESULTS
1. Mechanical stress-initiated PDGF ? receptor phosphorylation
2. Mechanical stress activated MAPKs signaling leading to both VSMC proliferation and
apoptosis
RESULTS
3. Mechanical stress induced protein kinase C translocation in SMCs
RESULTS
Identification of PKC ? knockout in VSMCs
RESULTS
PKC ? -/-
In VSMC
PKC ? +/+
In VSMC
PKC ? -/- resulted in actin fiber lose in VSMCs
RESULTS
PKC ? -/- blocked phosphorylation of migration-related proteins in VSMCs induced by SS
RESULTS
PKC ? -/- blocked migration and proliferation of VSMCs in response to SS
RESULTS
0w 8w
Mechanical stress induced venous bypass graft atheroma in vivo
RESULTS
P53-/- accelerated venous bypass graft atheroma induced by SS in vivo
RESULTS
ApoE-/- accelerated venous bypass graft atheroma induced by SS in vivo
RESULTS
ApoE+/+
0w 8w
ApoE-/-, 8w
SIGNAL PATHWAYS OF MECHANICAL STRESS
TRK
Ras/Rac
MAPK
Gene Expression
Proliferation
Migration
GPCR
G Proteins
PKC
Integrin
FAK
Paxillin
Vinculin
MECHANICAL STRESS
???
???
???
TRK: Tyrosine receptor kinase
GPCR: G protein coupled receptor
MAPK: Mitogen-activated protein kinase
PKC: Protein kinase C
FAK: Focal adhension kinase
CONCLUSION
Biomechanical stresses can initiate multi-intracellular signal pathways like growth factors, vas-active peptides leading to cardiovascular remodeling
Arteriosclerotic factors (e.g., ApoE-/-, and p53-/-) can accelerate mechanical stresses-induced cardiovascular remodeling
Yanhua Hu
Gertraud Sturm
Ursula Huemer
Gottfried Baier
Qingbo Xu
Manuel Mayr
Anya Jenewen
Thomas Ottl
ACKNOWLEGMENTS
Georg Wick
Institute of Biomedical Aging Research, Austrian Academy of Sciences, Austria
Proofs concerning SS-induced vascular remodeling
1. Hypertension induced pathological changes of multi-organs
2. Levels of increased blood pressure are positively related to mortality and morbidity
INTRODUCTION
INTRODUCTION
Proofs concerning SS-induced vascular remodeling
3. Spontaneous atherosclerotic lesion occurred preferentially at bifurcation and curvatures (disturbed hemodynamic forces)
4. Restenosis occurs after surgical interventions---angioplasty and venous bypass grafts ( elevated 10-fold mechanical forces )
Strategic Planning of Complete Gene Knockout
Microinjection of selected ES cells
Chimeric mouse production
Embryonic transfer
Production and maintenance of congenic mouse line
Functional consequences
This study will be very useful for understanding basic molecular mechanism underlining stretch stress-induced vascular remodeling and discovering new drug targets to treat hypertension
Bifurcation
Curvature
3. Protein kinase C mediates mechanical stress-induced vascular remodeling
RESULTS
PKC is am important mediator of cell proliferation, apoptosis and cell differentiation in response to many factors and downstream molecules of G protein signal pathways.
Three groups:
1. Conventional
(?, ?1, ?2, ? )
2. Novel
(?, ?, ?, ?, ?)
3. Atypical
(?, ?, ?)