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Vascular Smooth MuscleVascular Smooth Muscle
Dr. Dee Van Riper: MS113A
(ref. Rhoades & Bell; Chapter 8,
pgs.160-167, Chapter 15, 285-287)
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Learning ObjectivesLearning Objectives
Structure of vascular smooth muscle, both intracellular and
organ specific
Properties and regulation of vascular smooth muscle E/C
coupling (compared to striated muscles)
Understand blood vessel function on a cellular basis
Vascular smooth muscle cell/endothelial cell interactions
Mechanisms of action of vasodilators
Physiological and pathophysiological
structural adaptations of blood vessels
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Main functional cell type of blood vessels Maintains blood vessel tone (BP/compliance) and diameter (flow/blood
distribution) Target of several pharmacological agents Synthetic capacity
Highly plastic can alter phenotype to respond to changesphysiological demands Undergoes functional adaptation which can lead to development of
pathophysiologies.
Vascular Smooth Muscle (VSM)Vascular Smooth Muscle (VSM)
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Blood Vessel Organ StructureBlood Vessel Organ Structure
intima: luminal side of internal elastic lamina; endothelial cells forma non-thrombogenic, semi-permeable layer lining blood vessels
media: smooth muscle cells form a layered contractile structure, makeand remodel extracellular matrix (collagen, elastin, fibronectin)
adventitia: distal to external elastic lamina; fibroblasts form aloose, matrix-rich coating, contains nerves and in of larger vessels,microvessels (vaso vasorum)
IEL
EEL
Lumen
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Structural VariationStructural Variation
conduitcapacitance
resistance
exchange
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VSM Cell PropertiesVSM Cell Properties
Phenotypically diverse with respect to both morphology andbiochemical characteristics, i.e. variable contractile, secretory,migratory and growth phenotypes
Contractile proteins are not organized in the same way as striatedmuscle so there are no visible striations or sarcomeres smooth
muscle
Differentiated cells express specific forms and large amounts of contractile proteins (actins, myosins, regulatory proteins)
Small spindle or ribbon shaped cells
(3-5 m diam. X 100-300 m long)
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Smooth Muscle Tissue MorphologiesSmooth Muscle Tissue Morphologies
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Smooth Muscle Cellular StructureSmooth Muscle Cellular Structure
In arteries and veins, VSMcells are arranged in series
Active force is transmitted
cell:cell, cell:matrix:cell
Dense bodies=Z discs, -actinin, actin binding
Functional sarcomeresbetween dense bodies
dense plaques
Connection to extracellular domain through
membrane-spanning proteins called integrins
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Regulation of VSM cell functionRegulation of VSM cell function development of tonedevelopment of tone
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CONSTRICTION DILATION
Maintenance of flow and pressure
Provide sufficient perfusion to supply nutrients,
O2, and remove waste from tissues
protect from wide fluctuations in pressure and
flow
many feedback and regulatory processes
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Regulation of
vascular smoothmuscle tone
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Regulation of
vascular smoothmuscle tone
Rarely only onemechanism
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Myogenic tone independent of nerves, local or systemicagents. Development of tone in response to radial stretch of the blood vessel. More prominent in smaller vessels;mechanism based on activation of stretch-operated Ca ++channels and membrane depolarization.
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200 m
Resistance artery mounted in pressure myograph
bathed in physiological solution, oxygenated, 37.
Myogenic tone demonstrated in laboratorysetting free from any modulating factors.
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VASCULAR MYOGENIC TONE
Luminal pressure
D i a m e t e r
ActiveForce
Ca ++
free
Full Ca ++
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Neural Processes
Innervation and regulation through autonomic nervous system both sympathetic and parasymapthetic.
Several mechanisms used to modulate neural control
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Innervation pathways display a range of patterns
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Other bases of variation include: amount of neurotransmitterreleased, distance from varicosity to muscle cell, density of receptors, and relative population of disposal mechanisms.
Angiotensin II, NE, histamine,serotonin, inflammatory mediators
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Activation by Calcium
Actin m yosin interaction
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Actin myosin interaction striated m uscle
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VSM Regulation VSM Regulation -- sequencesequence
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in tonic smooth muscle, forcecan be maintained after Ca 2+
levels diminish latch is an energy efficientmechanism for sustaining
vascular tone over long periods
mechanisms underlying latch are not fully understood
may be based on attched,dephosphorylated cross-bridges, or slowly cyclingcrossbridges.
LATCH
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VSM
Striated Muscle
[myosin]Fo
(force)
Vo (velocity)
Myosin ATPase
0.25 11 1
0.1
1
0.1
1
VSM is strong, slow, and energy efficient
VSM Cell Properties VSM Cell Properties -- energeticsenergetics
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Regulation of VSM CaRegulation of VSM Ca 2+2+
store operated chstretch operated ch
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Regulation of VSM CaRegulation of VSM Ca 2+2+ :: CaCa 2+ 2+ Entry Entry
Ca2+ entry across plasmamembrane via several Ca 2+channels.
GPCR mediate Ca 2+ release fromsarcoplasmic reticulum stores viaIP3-gated channel. Variable contribution of Ca ++ -induced Ca ++ release
store operated chstretch operated ch
NE, EPI, AII, Et-1
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removal of vasoconstrictors decreases Ca 2+influx and release, allowing pumps to returnCa2+ to resting levels
Ca2+ re-uptake into sarcoplasmic reticulumstores via a specific ATPase (SERCA)
Ca2+ exit across plasma membrane via
Ca2+ ATPase energy consuming pump,tonically active, minimally regulated
Ca2+ /Na + exchanger passive bi-
directional exchanger
Na+ balance restored by Na + /K + ATPase
Regulation of VSM CaRegulation of VSM Ca 2+2+ ::Uptake/Exit and RelaxationUptake/Exit and Relaxation
Calcium exit
SR
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Most endogenous vasodilators relax VSM through formation
of the cyclic nucleotides cAMP and cGMP. These aresynthesized by their respective cyclases and act bystimluation of protein kinases PKA and PKG. These agentshave some actions in common as well as individual
activities.
Ca++ - independent relaxation
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CaCa++++
independentindependentvasodilationvasodilation ::cycliccyclic --nucleotidenucleotide
((cAMP,cGMPcAMP,cGMP )) mediatedmediated
PKAPKG
Both stimulate SERCA;PKA affects MLCK activity, PKG enhancesmyosin phosphatase
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Physiology of vascular endothelium
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Endothelial Modulation of Vascular FunctionEndothelial Modulation of Vascular Function
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Endothelial Modulation of Vascular FunctionEndothelial Modulation of Vascular Function
Endothelium interacts with blood:
Maintains a slick; surface; lossexposes a sticky substrate
Shear stress provides tonicstimluation release of PGI 2, NO
May play a more prominentrole in isolated areas of injury,inflammation, or disease
Endothelial cells variedthroughout the body
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Angiotensin converting enzyme (ACE) inhibitors are an importantclass of antihypertensive agents
Endothelial cells metabolize vasoactive agents
Endothelial Modulation of Vascular FunctionEndothelial Modulation of Vascular Function
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Nitric OxideNitric Oxide : an Important Endothelial Vasodilator : an Important Endothelial Vasodilator
NO is produced in EC in
response to agonist-mediatedelevation of [Ca 2+ ]i
NO diffuses to VSM andstimulates production of cGMP
cGMP (via PKG) activatesmyosin-LC phosphatase leadingto myosin-LC dephosphorylation
and relaxation
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Vascular Tone: the net effect of Vascular Tone: the net effect of
vasocontrictorsvasocontrictors
and vasodilatorsand vasodilators
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Vascular Adaptation andpathophysiology
Vascular smooth muscle is not terminally differentiated it displays remarkable plasticity. It can rapidly respond to
changing physiological demands, but in cases of chronicor long-term influences, a matched remodeling or phenotypic modulation is invoked. A prime example of this is restenosis
following balloon angioplasty.
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A. Representation of neointima formation. After vascular injury there is smooth musclephenotypic modulation (shape change; L lumen, arrow: IEL)
B. H/E stained sections showing increased neointima formation resulting in lumenalnarrowing. 1,2,3 refer to adventitia, media, neointima.
C. Photomicrographs showing staining (red-brown) of SM alpha-actin; expression isreduced in the media and upregulated in the neointima; arrows - IEL
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Vascular Vascular
RemodelingRemodeling
Medial wallhypertrophy
Eutrophic
Remodeling
hypertensionChroniclow flow
Chronichigh flow
exercise
Myointimal
hyperplasia
Plaque
injuryatherosclerosis
Aneurysm: excessive VSMprotease activity, degradation of extracellular matrix, and
weakening of the medial wall
Hypertrophy : increased VSMgrowth in response to greatermechanical load (pressure);leads to increased M/L ratio
E d th li l D f ti d CV DiE d th li l D f ti d CV Di
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Endothelial Dysfunction and CV DiseaseEndothelial Dysfunction and CV Disease
, vascular wall remodeling
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Vasoactive
Pharmacology
Vasoconstrictors:ephedrine, phenylephrine,pseudoephedrine
- increase blood pressure- reduce local blood flow
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Vasoactive
agents Vasodilators
Antagonists of constrictors:
Angiotensin II: converting enzymeinhibitors, ACE inhibitors ( captopril,enalopril ), receptor blockers(Losartan )
-adrenergic blockers ( tolazoline, phentolamine )
Drugs that block Ca2+ channels,
(verapamil, nifedipine ) Loop diuretics relax capacitancevessels (mechanism unknown)
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Vasoactive
agents Vasodilators (contd)
Cyclic nucleotide stimulation
cAMP: -adrenegic agonists ( isoproterenol,salbutamol ), PDE inhibitors ( methyxanthines )
cGMP: Drugs that release NO nitroglycerin,nitroprusside, sildenafil (Viagra)
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