Vascular Smooth Muscle

8/6/2019 Vascular Smooth Muscle

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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)

[email protected]


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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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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



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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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Vascular Smooth Muscle

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