Effects of Effects of Microgravity on Microgravity on

Vascular Vascular Adaptation Adaptation Steven Asplund, Xinli Hu, JoAnn Lin, Steven Asplund, Xinli Hu, JoAnn Lin,

Victor TsengVictor Tseng

Department of BioengineeringDepartment of Bioengineering

University of WashingtonUniversity of Washington

Invited Review PaperInvited Review Paper

Vascular adaptation to Vascular adaptation to microgravity: what have we microgravity: what have we learned? learned? Zhang, Li-Fan.Zhang, Li-Fan.

Review PaperReview Paper Presentation of past experiments - no Presentation of past experiments - no

explicit conclusionsexplicit conclusions

Introduction - BasicsIntroduction - Basics 1. Microgravity Conditions1. Microgravity Conditions

Results in orthostatic intolerance: Results in orthostatic intolerance: (inability to maintain standing upright)(inability to maintain standing upright)

2. Symptoms2. Symptoms Syncope (faint reflex) from decreased Syncope (faint reflex) from decreased

tolerancetolerance Decreased aerobic capacityDecreased aerobic capacity

3. Reversal of Effects3. Reversal of Effects Orthostatic intolerance is temporary…Orthostatic intolerance is temporary… … … What about longer periods of space What about longer periods of space

travel?travel?

Introduction – TermsIntroduction – Terms HUHU Hind-limb unloadingHind-limb unloading LBNPLBNP Lower Body Negative Lower Body Negative

PressurePressure FVRFVR Forearm Vascular ResistanceForearm Vascular Resistance TPRTPR Total Peripheral ResistanceTotal Peripheral Resistance CSACSA Cross-Sectional AreaCross-Sectional Area HDTHDT Head Down TiltHead Down Tilt SMCSMC Smooth Muscle CellsSmooth Muscle Cells HSPHSP Heat Shock ProteinsHeat Shock Proteins CSFCSF Cerebral Spinal FluidCerebral Spinal Fluid

Introduction - HistoryIntroduction - History

1. Current Paradigm1. Current Paradigm Hypovolemia (reduced volume of circulating Hypovolemia (reduced volume of circulating

blood)blood) Factor: Increased venous compliance (sub-thoracic)Factor: Increased venous compliance (sub-thoracic) Factor: Decreased baroreceptor sensitivityFactor: Decreased baroreceptor sensitivity

2. New Evidence2. New Evidence Degradation of vasoconstrictor regulation Degradation of vasoconstrictor regulation

systemssystems Factor: Receptor changeFactor: Receptor change

Structural changes in the vascular systemStructural changes in the vascular system Factor: Change in hemodynamicsFactor: Change in hemodynamics

Introduction - ObjectivesIntroduction - Objectives

1. Objectives:1. Objectives: Understand other causes Understand other causes

contributing to orthostatic contributing to orthostatic intolerance intolerance

Changes in dynamics of Changes in dynamics of peripheral resistanceperipheral resistance

Review experiments & Review experiments & hypotheses presented in hypotheses presented in paperpaper

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Introduction – Introduction – MicrogravityMicrogravity

1. Space Travel1. Space Travel Exposure to less than Exposure to less than

1G1G

2. Effects of 2. Effects of microgravity on microgravity on blood distributionblood distribution Transmural pressure Transmural pressure

changeschanges Hemodynamics Hemodynamics

alteredaltered

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Experimental MethodsExperimental Methods

1. Human Subjects1. Human Subjects Returning Returning

astronautsastronauts Bed RestBed Rest

2. Rodents2. Rodents Tail suspensionTail suspension Hind limb unloading Hind limb unloading

(HU)(HU)

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Vascular Vascular StructureStructure Changes Changes

Under Microgravity ExposureUnder Microgravity Exposure Under extended exposure to Under extended exposure to

microgravity, vascular system remodels microgravity, vascular system remodels its structure.its structure.

Structural changes respond to Structural changes respond to hemodynamic changes:hemodynamic changes: Blood pressureBlood pressure Blood flowBlood flow

Changes intended to maintain constant Changes intended to maintain constant normal and shear stresses in blood normal and shear stresses in blood vesselsvessels

Why change in Why change in structure?structure?

1972 hypothesis:1972 hypothesis: Human structure (vascular, Human structure (vascular,

musculoskeletal) has adapted to 1G. musculoskeletal) has adapted to 1G. Under microgravity, Under microgravity, hydrostatichydrostatic

pressure gradient and pressure gradient and gravitationalgravitational pressure gradient disappearpressure gradient disappear

Effective pressure: Effective pressure: <1 G in lower region – atrophy<1 G in lower region – atrophy >1 G in upper region – hypertrophy >1 G in upper region – hypertrophy

How is structure How is structure remodeled?remodeled?

Change in BP changes wall thicknessChange in BP changes wall thickness Change in flow changes vessel diameterChange in flow changes vessel diameter

Shear stress up- or Shear stress up- or down- regulates gene down- regulates gene expression of growth expression of growth factorsfactors

Paracrines promote Paracrines promote or inhibit SMC or inhibit SMC growthgrowth

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Experiments on Vascular Experiments on Vascular Remodeling:Remodeling:

Goal: to observe differential adaptation Goal: to observe differential adaptation to microgravity in forebody and lower to microgravity in forebody and lower body vasculaturesbody vasculatures

Experimental Setup: Experimental Setup: Tail-suspended, hind-limb unloaded Tail-suspended, hind-limb unloaded

rat modelrat model Exposed to microgravity for 4 weeksExposed to microgravity for 4 weeks 1 week recovery1 week recovery

Isolated muscle cell studyIsolated muscle cell study

ResultsResults1. Conduit arteries (major)1. Conduit arteries (major)

Lower body arteries (femoral, tibial):Lower body arteries (femoral, tibial):

During exposure to microgravity:During exposure to microgravity: ReductionReduction in: diameter, CSA, number of in: diameter, CSA, number of

layers of SMC, number of myofilament in layers of SMC, number of myofilament in SMC (general SMC (general atrophyatrophy))

Upper body arteries (common carotid, basilar Upper body arteries (common carotid, basilar artery)artery) IncreaseIncrease in: hyperplasia, layers of SMC, in: hyperplasia, layers of SMC,

conversion of contractile to synthetic conversion of contractile to synthetic phenotype (general phenotype (general hypertrophyhypertrophy))

Both regions: alterations restored after 1 week Both regions: alterations restored after 1 week recoveryrecovery

ResultsResults2. Small arteries/arterioles2. Small arteries/arterioles

Studies done in isolated muscle cellsStudies done in isolated muscle cells Hind-limb unloading does not Hind-limb unloading does not uniformlyuniformly

affect all vesselsaffect all vessels

Type IIb (fast-twitch): no structural changeType IIb (fast-twitch): no structural change

Type I (slow-twitch): decreased maximal Type I (slow-twitch): decreased maximal diameterdiameter

Endothelial cell morphology:Endothelial cell morphology: Femoral arteries: cell length decreased, width Femoral arteries: cell length decreased, width

increased during exposureincreased during exposure Common carotid arteries: length increased, Common carotid arteries: length increased,

width decreasedwidth decreased All alteration restored after recoveryAll alteration restored after recovery

FunctionFunctionMain IdeasMain Ideas

The peripheral resistance is The peripheral resistance is determined by the functions of determined by the functions of three major components:three major components: Response of vascular smooth muscle Response of vascular smooth muscle

to autonomic systemto autonomic system Density of innervating fibersDensity of innervating fibers Response to paracrines (myogenic Response to paracrines (myogenic

autoregulation)autoregulation) Microgravity decreases the Microgravity decreases the

dynamic range of vasocontriction dynamic range of vasocontriction and vasodilation. and vasodilation.

FunctionFunctionResponse to Sympathetic Response to Sympathetic

SystemSystem αα22 and and ββ22 adrenergic receptors become adrenergic receptors become

hypersensitive due to decreased tonic nor-hypersensitive due to decreased tonic nor-epinephrine and epinephrine (moves kinetics epinephrine and epinephrine (moves kinetics close to Kclose to KMM). ). Hypothesis:Hypothesis:

Astronauts with a hypoactive sympathetic Astronauts with a hypoactive sympathetic background experienced syncope. background experienced syncope.

β2 affinity becomeshigher than α2 affinity for E/NE

Inability to constrict arterioles

Vascular resistance remains low

FunctionFunctionHypothesis on Sympathetic Hypothesis on Sympathetic

ChangesChanges Might be other causes other than Might be other causes other than

the catecholaminesthe catecholamines Some calcium channels opened by Some calcium channels opened by

smooth muscle stretchsmooth muscle stretch Changes in the transduction Changes in the transduction

pathways: MLC kinase, IPpathways: MLC kinase, IP33, , membrane channels, calcium membrane channels, calcium dependent channelsdependent channels

Spontaneous contraction rate Spontaneous contraction rate decreasesdecreases

FunctionFunctionResponse to Parasympathetic Response to Parasympathetic

SystemSystem In rates, decreased ability to dilate In rates, decreased ability to dilate

hindlimb vessels with stimulation hindlimb vessels with stimulation by vasodilators (Ach.)by vasodilators (Ach.) Thus, it seems that intolerance is Thus, it seems that intolerance is

caused by the caused by the dilationdilation inadequacy in inadequacy in the brain and the brain and constrictiveconstrictive inadequacy inadequacy in the lower regions.in the lower regions.

May contribute to decreased May contribute to decreased aerobic capacity, since RBC aerobic capacity, since RBC transport is inhibited.transport is inhibited.

However, some experiments show However, some experiments show no change seen in response of no change seen in response of cranial arteries. cranial arteries.

FunctionFunctionHypothesis on Hypothesis on

Parasympathetic ChangesParasympathetic Changes Probably involves interference Probably involves interference

with the relaxation mechanismwith the relaxation mechanism Changes in calmodulin, myosin Changes in calmodulin, myosin

phosphatase, calcium pump kineticsphosphatase, calcium pump kinetics Locked in the latch stateLocked in the latch state

Might be caused by changes in Might be caused by changes in tonic levels of the choline, tonic levels of the choline, changing affinity of receptorschanging affinity of receptors

FunctionFunctionParacrinesParacrines

Reduction of endothelial NO Reduction of endothelial NO synthase expression in the synthase expression in the hindlimb and cranial arteries hindlimb and cranial arteries Reduced vasodilation responseReduced vasodilation response Overall increase in contractile toneOverall increase in contractile tone

Dilation in response to adenosine Dilation in response to adenosine (local hypoxia) arterioles (local hypoxia) arterioles supplying FF fibers greater than supplying FF fibers greater than at slow fibers. at slow fibers.

FunctionFunctionDistribution of Post-ganglionic Distribution of Post-ganglionic

EfferentsEfferents Density of adrenergic fibers Density of adrenergic fibers

decreased in the caudal area but decreased in the caudal area but increased above normal during increased above normal during recoveryrecovery

Density of adrenergic fibers Density of adrenergic fibers increased in the rostral area but increased in the rostral area but decreased below normal during decreased below normal during recoveryrecovery

The acute effect: limits The acute effect: limits constriction or dilationconstriction or dilation

FunctionFunctionThe Whole EffectThe Whole Effect

What happens to “contractility”:What happens to “contractility”: 40% increase in anterior arteriolar force of contraction40% increase in anterior arteriolar force of contraction 60% decrease decrease in posterior60% decrease decrease in posterior

Results in smaller range of contraction and Results in smaller range of contraction and dilation.dilation.

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SolutionsSolutions

Limited successLimited success Acute intense exerciseAcute intense exercise Treadmill in LBNP Treadmill in LBNP

chamberchamber αα- and - and ββ- adrenergic - adrenergic

agonistsagonists Thigh cuffsThigh cuffs Intermittent exposure Intermittent exposure

to artificial gravityto artificial gravity

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Solutions – ExerciseSolutions – Exercise

Acute and intenseAcute and intense Limited benefit to prevent Limited benefit to prevent

cardiovascular deconditioningcardiovascular deconditioning Hypothesis: Altered distribution of Hypothesis: Altered distribution of

pressure and flow causes sustained pressure and flow causes sustained alterations in the vascular local alterations in the vascular local stress conditionsstress conditions

May be the cause of structural and functional May be the cause of structural and functional changes in vascular smooth musclechanges in vascular smooth muscle

Cannot be corrected with exercise aloneCannot be corrected with exercise alone

Solutions - ExerciseSolutions - Exercise Overall hemodynamic condition and Overall hemodynamic condition and

tissue stress distribution for vessels and tissue stress distribution for vessels and cardiac muscle may stimulate cardiac muscle may stimulate restoration of blood pressure regulationrestoration of blood pressure regulation Needs further studyNeeds further study

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Solutions - Treadmill in Solutions - Treadmill in LBNP ChamberLBNP Chamber

LBNP: lower body LBNP: lower body negative pressurenegative pressure

May correct lower body May correct lower body pressurespressures

Cannot correct cerebral Cannot correct cerebral vessel pressurevessel pressure

Proposal to integrate Proposal to integrate LBNP with respiration at LBNP with respiration at negative pressurenegative pressure Restore gradients of blood Restore gradients of blood

pressure along the body axispressure along the body axishttp://spacebio.net/modules/cc_resource/reed/CardioPPt/sld032.htm

LBNP on Treadmill

Solutions - Solutions - αα- and - and ββ- - adrenergic Agonistsadrenergic Agonists

Normal vasocontrictor response leads to Normal vasocontrictor response leads to reduced vasopressor response because reduced vasopressor response because ββ22--hypersensitivity is greater than hypersensitivity is greater than αα22--hypersensitivity (local receptor sensitivity hypersensitivity (local receptor sensitivity degradation)degradation)

Enhanced vascular Enhanced vascular ββ-adrenergic response-adrenergic response Propranolol (Propranolol (ββ-receptor antagonist) – limited -receptor antagonist) – limited

improvement in countering cardiovascular improvement in countering cardiovascular deconditioningdeconditioning

Infusion of Infusion of αα- and - and ββ-adrenergic agonists unchanged -adrenergic agonists unchanged in astronautsin astronauts

Inconclusive: negative results, but experiment run 24-28 Inconclusive: negative results, but experiment run 24-28 hrs. after return to 1 Ghrs. after return to 1 G

Solutions - Thigh CuffsSolutions - Thigh Cuffs

May correct fluid May correct fluid distributiondistribution

Does not correct Does not correct pressure pressure distribution across distribution across arteriolesarterioles

Relation to Relation to hypovolemiahypovolemia Head-down bed rest Head-down bed rest

studiesstudies Restoration of Restoration of

plasma volume plasma volume alone did not restore alone did not restore orthostatic toleranceorthostatic tolerance

May be due to May be due to increased venous increased venous compliancecompliance

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Solutions - Intermittent Solutions - Intermittent Exposure to Artificial Exposure to Artificial

GravityGravity Intermittent exposure to gravity may Intermittent exposure to gravity may

counteract effects of microgravitycounteract effects of microgravity Continuous exposure not necessaryContinuous exposure not necessary Short-arm centrifuge runs at +Gz (footward G) Short-arm centrifuge runs at +Gz (footward G)

acceleration effective for bed rest or dry acceleration effective for bed rest or dry immersionimmersion

2h/day standing may be sufficient to prevent 2h/day standing may be sufficient to prevent orthostatic intolerance in head-down bed rest orthostatic intolerance in head-down bed rest studiesstudies

More exposure (4-6h/day) may be necessary to More exposure (4-6h/day) may be necessary to prevent mass reduction of soleus muscleprevent mass reduction of soleus muscle

4h/day standing or head-up tilt partially 4h/day standing or head-up tilt partially effective in preventing adverse bone changeseffective in preventing adverse bone changes

SummarySummary 1. Besides hypovolemia, major factors 1. Besides hypovolemia, major factors

in faintingin fainting Altered structureAltered structure

Venous complianceVenous compliance Muscle atrophy (smooth/skeletal)Muscle atrophy (smooth/skeletal)

Altered functionAltered function Limited Vasodilatation/Vasoconstriction Limited Vasodilatation/Vasoconstriction

responseresponse Hormonal levelHormonal level Innervation levelInnervation level

2. Solutions2. Solutions Intermittent exposure to artificial gravity may Intermittent exposure to artificial gravity may

be necessary for long-term space flightsbe necessary for long-term space flights No practical and effective solutions found yetNo practical and effective solutions found yet

ReferencesReferences Zhang, Li-Fan. Vascular adaptation to Zhang, Li-Fan. Vascular adaptation to

microgravity: what have we learned? microgravity: what have we learned? J. Appl. J. Appl. PhysiolPhysiol. (2001) 91: 2415-2430.. (2001) 91: 2415-2430.

Schultz, James. “Vascular Health in Space.” Schultz, James. “Vascular Health in Space.” NASA: Exploration Systems Mission Directorate NASA: Exploration Systems Mission Directorate Education OutreachEducation Outreach. . http://weboflife.nasa.gov/currentResearch/currenhttp://weboflife.nasa.gov/currentResearch/currentResearchFlight/vascular.htm. Accessed 2 Mar. tResearchFlight/vascular.htm. Accessed 2 Mar. 2006.2006.