Effects of Microgravity on Vascular Adaptation Steven Asplund, Xinli Hu, JoAnn Lin, Victor Tseng...
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Transcript of Effects of Microgravity on Vascular Adaptation Steven Asplund, Xinli Hu, JoAnn Lin, Victor Tseng...
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
http://spaceresearch.nasa.gov/research_projects/images/bioastronautics_03-2002_1.jpg
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
http://upload.wikimedia.org/wikipedia/commons/thumb/8/88/Astronaut-EVA.jpg/300px-Astronaut-EVA.jpg
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)
http://quest.arc.nasa.gov/neuron/photos/images/rat.gif
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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
http://files2.turbosquid.com/Preview/Content_on_12_2_2003_20_40_37/Blood_vessel_thumb01.JPGc03597a8-8443-4c69-95e2-20da76bd6dbe.jpgLarge.jpg
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.
http://www.mastersmensclinic.com/cardiovascularhealth_files/image015.jpg
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
http://www.tiscali.co.uk/reference/encyclopaedia/ hutchinson/images/0008n031.jpg
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.