Effects of Microgravity on Vascular Adaptation

1. Effects of Microgravity on Vascular Adaptation Steven Asplund, Xinli Hu, JoAnn Lin, Victor Tseng Department of Bioengineering University of Washington

2. Invited Review Paper • Vascular adaptation to microgravity: what have we learned? Zhang, Li-Fan. • Review Paper • Presentation of past experiments - no explicit conclusions

3. Introduction - Basics • 1. Microgravity Conditions • Results in orthostatic intolerance: • (inability to maintain standing upright) • 2. Symptoms • Syncope (faint reflex) from decreased tolerance • Decreased aerobic capacity • 3. Reversal of Effects • Orthostatic intolerance is temporary… • … What about longer periods of space travel?

4. Introduction – Terms • HU Hind-limb unloading • LBNP Lower Body Negative Pressure • FVR Forearm Vascular Resistance • TPR Total Peripheral Resistance • CSA Cross-Sectional Area • HDT Head Down Tilt • SMC Smooth Muscle Cells • HSP Heat Shock Proteins • CSF Cerebral Spinal Fluid

5. Introduction - History • 1. Current Paradigm • Hypovolemia (reduced volume of circulating blood) • Factor: Increased venous compliance (sub-thoracic) • Factor: Decreased baroreceptor sensitivity • 2. New Evidence • Degradation of vasoconstrictor regulation systems • Factor: Receptor change • Structural changes in the vascular system • Factor: Change in hemodynamics

6. Introduction - Objectives • 1. Objectives: • Understand other causes contributing to orthostatic intolerance • Changes in dynamics of peripheral resistance • Review experiments & hypotheses presented in paper http://spaceresearch.nasa.gov/research_projects/images/bioastronautics_03-2002_1.jpg

7. Introduction – Microgravity • 1. Space Travel • Exposure to less than 1G • 2. Effects of microgravity on blood distribution • Transmural pressure changes • Hemodynamics altered http://upload.wikimedia.org/wikipedia/commons/thumb/8/88/Astronaut-EVA.jpg/300px-Astronaut-EVA.jpg

8. Experimental Methods • 1. Human Subjects • Returning astronauts • Bed Rest • 2. Rodents • Tail suspension • Hind limb unloading (HU) http://images.spaceref.com/news/2005/WISE.ESA_L.jpg http://quest.arc.nasa.gov/neuron/photos/images/rat.gif

9. Vascular Structure Changes Under Microgravity Exposure • Under extended exposure to microgravity, vascular system remodels its structure. • Structural changes respond to hemodynamic changes: • Blood pressure • Blood flow • Changes intended to maintain constant normal and shear stresses in blood vessels

10. Why change in structure? • 1972 hypothesis: • Human structure (vascular, musculoskeletal) has adapted to 1G. • Under microgravity, hydrostatic pressure gradient and gravitational pressure gradient disappear • Effective pressure: • <1 G in lower region – atrophy • >1 G in upper region – hypertrophy

11. Change in BP changes wall thickness Change in flow changes vessel diameter Shear stress up- or down- regulates gene expression of growth factors Paracrines promote or inhibit SMC growth How is structure remodeled? http://files2.turbosquid.com/Preview/Content_on_12_2_2003_20_40_37/Blood_vessel_thumb01.JPGc03597a8-8443-4c69-95e2-20da76bd6dbe.jpgLarge.jpg

12. Experiments on Vascular Remodeling: • Goal: to observe differential adaptation to microgravity in forebody and lower body vasculatures • Experimental Setup: • Tail-suspended, hind-limb unloaded rat model • Exposed to microgravity for 4 weeks • 1 week recovery • Isolated muscle cell study

13. Results1. Conduit arteries (major) • Lower body arteries (femoral, tibial): During exposure to microgravity: • Reduction in: diameter, CSA, number of layers of SMC, number of myofilament in SMC (general atrophy) • Upper body arteries (common carotid, basilar artery) • Increase in: hyperplasia, layers of SMC, conversion of contractile to synthetic phenotype (general hypertrophy) • Both regions: alterations restored after 1 week recovery

14. Results2. Small arteries/arterioles • Studies done in isolated muscle cells • Hind-limb unloading does not uniformly affect all vessels Type IIb (fast-twitch): no structural change Type I (slow-twitch): decreased maximal diameter • Endothelial cell morphology: • Femoral arteries: cell length decreased, width increased during exposure • Common carotid arteries: length increased, width decreased • All alteration restored after recovery

15. FunctionMain Ideas • The peripheral resistance is determined by the functions of three major components: • Response of vascular smooth muscle to autonomic system • Density of innervating fibers • Response to paracrines (myogenic autoregulation) • Microgravity decreases the dynamic range of vasocontriction and vasodilation.

16. FunctionResponse to Sympathetic System • α2 and β2 adrenergic receptors become hypersensitive due to decreased tonic nor-epinephrine and epinephrine (moves kinetics close to KM). • Hypothesis: • Astronauts with a hypoactive sympathetic background experienced syncope. β2 affinity becomes higher than α2 affinity for E/NE Vascular resistance remains low Inability to constrict arterioles

17. FunctionHypothesis on Sympathetic Changes • Might be other causes other than the catecholamines • Some calcium channels opened by smooth muscle stretch • Changes in the transduction pathways: MLC kinase, IP3, membrane channels, calcium dependent channels • Spontaneous contraction rate decreases

18. FunctionResponse to Parasympathetic System • In rates, decreased ability to dilate hindlimb vessels with stimulation by vasodilators (Ach.) • Thus, it seems that intolerance is caused by the dilation inadequacy in the brain and constrictive inadequacy in the lower regions. • May contribute to decreased aerobic capacity, since RBC transport is inhibited. • However, some experiments show no change seen in response of cranial arteries.

19. FunctionHypothesis on Parasympathetic Changes • Probably involves interference with the relaxation mechanism • Changes in calmodulin, myosin phosphatase, calcium pump kinetics • Locked in the latch state • Might be caused by changes in tonic levels of the choline, changing affinity of receptors

20. FunctionParacrines • Reduction of endothelial NO synthase expression in the hindlimb and cranial arteries • Reduced vasodilation response • Overall increase in contractile tone • Dilation in response to adenosine (local hypoxia) arterioles supplying FF fibers greater than at slow fibers.

21. FunctionDistribution of Post-ganglionic Efferents • Density of adrenergic fibers decreased in the caudal area but increased above normal during recovery • Density of adrenergic fibers increased in the rostral area but decreased below normal during recovery • The acute effect: limits constriction or dilation

22. What happens to “contractility”: 40% increase in anterior arteriolar force of contraction 60% decrease decrease in posterior Results in smaller range of contraction and dilation. FunctionThe Whole Effect http://www.mastersmensclinic.com/cardiovascularhealth_files/image015.jpg

23. Solutions • Limited success • Acute intense exercise • Treadmill in LBNP chamber • α- and β- adrenergic agonists • Thigh cuffs • Intermittent exposure to artificial gravity http://dwp.bigplanet.com/kschneider/nasapictures/view_alone.nhtml?profile=nasapictures&UID=10018

24. Solutions – Exercise • Acute and intense • Limited benefit to prevent cardiovascular deconditioning • Hypothesis: Altered distribution of pressure and flow causes sustained alterations in the vascular local stress conditions • May be the cause of structural and functional changes in vascular smooth muscle • Cannot be corrected with exercise alone

25. Solutions - Exercise • Overall hemodynamic condition and tissue stress distribution for vessels and cardiac muscle may stimulate restoration of blood pressure regulation • Needs further study http://www.tiscali.co.uk/reference/encyclopaedia/ hutchinson/images/0008n031.jpg

26. Solutions - Treadmill in LBNP Chamber LBNP on Treadmill • LBNP: lower body negative pressure • May correct lower body pressures • Cannot correct cerebral vessel pressure • Proposal to integrate LBNP with respiration at negative pressure • Restore gradients of blood pressure along the body axis http://spacebio.net/modules/cc_resource/reed/CardioPPt/sld032.htm

27. Solutions - α- and β- adrenergic Agonists • Normal vasocontrictor response leads to reduced vasopressor response because β2-hypersensitivity is greater than α2-hypersensitivity (local receptor sensitivity degradation) • Enhanced vascular β-adrenergic response • Propranolol (β-receptor antagonist) – limited improvement in countering cardiovascular deconditioning • Infusion of α- and β-adrenergic agonists unchanged in astronauts • Inconclusive: negative results, but experiment run 24-28 hrs. after return to 1 G

28. May correct fluid distribution Does not correct pressure distribution across arterioles Relation to hypovolemia Head-down bed rest studies Restoration of plasma volume alone did not restore orthostatic tolerance May be due to increased venous compliance Solutions - Thigh Cuffs http://www.trimlinemed.com/products/bainbridge/images/bain-2tubes-thigh.jpg

29. Solutions - Intermittent Exposure to Artificial Gravity • Intermittent exposure to gravity may counteract effects of microgravity • Continuous exposure not necessary • Short-arm centrifuge runs at +Gz (footward G) acceleration effective for bed rest or dry immersion • 2h/day standing may be sufficient to prevent orthostatic intolerance in head-down bed rest studies • More exposure (4-6h/day) may be necessary to prevent mass reduction of soleus muscle • 4h/day standing or head-up tilt partially effective in preventing adverse bone changes

30. Summary • 1. Besides hypovolemia, major factors in fainting • Altered structure • Venous compliance • Muscle atrophy (smooth/skeletal) • Altered function • Limited Vasodilatation/Vasoconstriction response • Hormonal level • Innervation level • 2. Solutions • Intermittent exposure to artificial gravity may be necessary for long-term space flights • No practical and effective solutions found yet

31. References • Zhang, Li-Fan. Vascular adaptation to microgravity: what have we learned? J. Appl. Physiol. (2001) 91: 2415-2430. • Schultz, James. “Vascular Health in Space.” NASA: Exploration Systems Mission Directorate Education Outreach. http://weboflife.nasa.gov/currentResearch/currentResearchFlight/vascular.htm. Accessed 2 Mar. 2006.