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Experiment Overview


Brief Summary

Commercial Biomedical Testing Module-3: STS-135 space flight's affects on vascular atrophy in the hind limbs of mice (CBTM-3-Vascular Atrophy) examines the effects of space flight on the skeletal bones of mice and the efficacy of a novel agent that may mitigate the loss of bone associated with space flight. Humans and animals have been observed to lose bone mass during the reduced gravity of space flight. CBTM-3-Vascular Atrophy specifically determines if there is a correlation between space flight induced altered blood supply to the bones and surrounding tissues with a resultant loss of bone mass.

Principal Investigator(s)

Ron Midura, Ph.D., Cleveland Clinic Foundation, Cleveland, OH, United States

Co-Investigator(s)/Collaborator(s)

Noel Patrick McCabe, Ph.D., Cleveland Clinic Foundation, Cleveland, OH, United States

Caroline Androjna, Cleveland Clinic Foundation, Cleveland, OH, United States

Developer(s)

NASA Ames Research Center, Moffett Field, CA, United States

Sponsoring Space Agency

National Aeronautics and Space Administration (NASA)

Sponsoring Organization

Human Exploration and Operations Mission Directorate (HEOMD)

Research Benefits

Information Pending

ISS Expedition Duration

March 2011 - September 2011

Expeditions Assigned

27/28

Previous ISS Missions

A similar investigation, CBTM, flew round trip to the ISS on STS-108 during ISS Expedition 4. CBTM-2 flew round trip to the ISS on STS-118 during ISS Expedition 15. AEMs have flown on numerous Space Shuttle missions over the years.

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Experiment Description

Research Overview

• The loss of bone mass during space flight remains a significant problem for human space flight, especially long-duration space flights.



• A variety of countermeasures has been tried but has not proven to be totally effective.



• A potential correlation between bone mass loss and blood supply to the bone has not been tested previously.



• Commercial Biomedical Testing Module-3: STS-135 space flight's affects on vascular atrophy in the hind limbs of mice (CBTM-3-Vascular Atrophy) is part of a suite of investigations that focus on the effects of space flight on bone, particularly skeletal bone.



• If a correlation between blood supply and bone mass is found, it opens new avenues of research into the mechanisms associated with skeletal physiology and regulation both during space flight and during ground-based bone disorders such as osteopenia, osteoporosis, spinal cord injury and others.

Description

Commercial Biomedical Testing Module-3: STS-135 space flight's affects on vascular atrophy in the hind limbs of mice (CBTM-3-Vascular Atrophy) only receives animals that have not received the therapeutic test agent. Therefore, CBTM-3-Vascular Atrophy compares untreated flight animals with animals that were held in AEM's on the ground during the flight. CBTM-3-Vascular Atrophy focuses on determining whether space flight results in vascular atrophy in the hind limbs leading to a decreased vascular presence and decreased blood supply to the bone and surrounding tissues. CBTM-3-Vascular Atrophy utilizes long bones of the animals provided postflight, specifically a region of the lower hindlimb at mid-calf; a 5-mm long region of interest (ROI) that includes portions of the tibia, fibula and attached skeletal muscles such as the soleus. The rationale for selecting this ROI is that unloading results in sarcopenia and osteopenia (muscle and bone mass loss) in this anatomical region. Samples of tissue are embedded in cryomedium, stained and examined for differences in vascular/blood supply, vessel tissue structure, and decalcification between flight and ground animals. Tissue sections from mouse lower hind limbs are also used to identify potential alterations in vascular cell gene expression as a consequence of space flight. Upon completion of the flight, the research team has access to the mice a few hours after landing.

Nine to ten week old female C57Bl6 mice fly onboard the STS-135 Space Shuttle mission in the CBTM-3 payload. The primary objective of this space mission is to evaluate a sclerostin antibody treatment to promote bone formation and mitigate bone loss in microgravity. This experiment is configured with three animal enclosure modules (AEMs) flown on STS-135 and an additional three AEMs that house ground control mice in the Space Life Sciences Laboratory at Kennedy Space Center. Each AEM contains ten mice.

This research is also expected to contribute data to the current body of research on microgravity effects on the skeletal, cardiovascular, and immune systems, liver and kidney function as well as other physiological systems through a tissue sharing program. Every effort will be made to harvest as many different samples and types of tissue from the mice as possible for other mission specific biomedical research. Positive results from this research may advance our understanding of mechanistic changes that occur in various physiological systems after exposure to microgravity and support overall efforts to reduce health risks to crewmembers. The investigations resulting from the CBTM-3 tissue sharing program are as follows:

• Brain
  • Alan R. Hargens, University of California San Diego, La Jolla CA
  • Michael Pecaut, Ph.D, Loma Linda University, Loma Linda, CA
  • Gregory A. Nelson, Ph.D. , Loma Linda University, Loma Linda, CA
  • Xiao Wen Mao, M.D., Loma Linda University, Loma Linda, CA
• Eyes
  • Susana B. Zanello, Ph.D., Universities Space Research Association, Houston, TX
  • Xiao Wen Mao, M.D., Loma Linda University, Loma Linda, CA
• Lung
  • Roberto Garofalo, M.D., University of Texas Medical Branch, Galveston, TX
  • Xiao Wen Mao, M.D., Loma Linda University, Loma Linda, CA
• Kidneys and Small Intestine
  • Moshe Levi, University of Colorado, Denver, CO
• Liver
  • Karen Jonscher, Ph.D.,  University of Colorado, Denver CO
  • Michael Pecaut, Ph.D, Loma Linda University, Loma Linda, CA
  • Jian Tian, Ph.D., Loma Linda University, Loma Linda, CA
  • Scott  M. Smith, Ph.D., Johnson Space Center, Houston, TX
  • Virginia E. Wotring, Ph.D., Universities Space Research Association, Houston, TX
• Metatarsals
  • Eduardo Almeida, Ph.D.,  Ames Research Center, Moffett Field, CA
• Distal Tibia and Tarsus
  • Hiroki Yokota, Ph.D., Indiana University-Purdue University Indianapolis, Indianapolis, IN
• Thymus
  • Millie Hughes-Fulford, Ph.D.,  University of California, San Francisco, San Francisco, CA
  • Daila S. Gridley, Loma Linda University, Loma Linda, CA
• Spleen
  • Millie Hughes-Fulford, Ph.D.,  University of California, San Francisco, San Francisco, CA
  • Michael Pecaut, Ph.D, Loma Linda University, Loma Linda, CA
• Extensor digitoum longus, transversus abdominis and masseter Muscle
  • Elisabeth R. Barton, Ph.D., University of Pennsylvania, Philadelphia, PA
• Temporal Bones
  • Richard D. Boyle, Ph.D., Universities Space Research Association, Moffett Field, CA
  • Larry F. Hoffman, Ph.D.,  University of California Los Angeles, Los Angeles, CA
  • Shin-ichi Usami, M.D., Shinshu University, Matsumoto, Japan
• Cerebral Artery, Mesenteric Vein, Heart, Soleus
  • Michael D. Delp, Ph.D.,  University of Florida, Gainesville, FL
• Adrenals
  • Michael Pecaut, Ph.D, Loma Linda University, Loma Linda, CA
• Femoral Heads, Quadriceps and Skin
  • David Fitzgerald, Ph.D.,  Oregon Health and Science University, Portland, OR
• Tail
  • Alan R. Hargens, University of California San Diego, La Jolla CA
• Heart, Soleus, Extensor digitoum longus and transversus abdominis
  • Brooke C. Harrison, Ph.D., University of Colorado, Boulder, CO
• Biceps brachii and Triceps brachi
  • Akihiko Ishihara, Ph.D.,  Kyoto University, Kyoto, Japan
• Skin
  • Xiao Wen Mao, M.D., Loma Linda University, Loma Linda, CA
  • Masahiro Terada, Japan Aerospace Exploration Agency, Tsukuba, Japan
• Uterine horn, ovaries, stomach
  • Joseph S. Tash, Ph.D., University of Kansas Medical Center, Kansas City, KS
• Distal Colon and Fecal Pellets
  • Scott  M. Smith, Ph.D., Johnson Space Center, Houston, TX
• Salivary glands and 1/4 the left ventricle
  • Maija Mednieks, Ph.D., University of Connecticut Health Center, Farmington, CT
• Humerus, rotator cuff, scapula units  and Achilles tendon calcaneus units
  • Stavros Thomopoulos, Ph.D., Washington University, St. Louis, MO
• Meniscus
  • Jeffrey Willey, Ph.D.,  Wake Forest School of Medicine, Winston-Salem, NC

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Applications

Space Applications

If a correlation is found between blood supply to bone and bone mass regulation, new insights into the mechanisms governing how the body responds to skeletal unloading will undoubtedly result. Such insights may lead to new therapies for maintaining a healthy musculoskeletal system during long-duration space flights.

Earth Applications

As noted in the preceding paragraph, if a correlation is found between blood supply to bone and bone mass regulation, new insights into the mechanisms governing how the body responds to skeletal unloading will likely result, insights that might lead not only to new therapies for maintaining a healthy musculoskeletal system during long duration space flights, but also new therapies for treating muscle and bone wasting diseases on the Earth.

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Operations

Operational Requirements

AEM's with ten mice each are requested for a late load (L-21 hours) and to be removed postflight within four hours of landing. During flight the crew is requested to conduct a daily health check of the animals, i.e., a visual observation through the Lexan lid of the AEMs. Unusual appearance of the animals is to be reported as soon as possible.

Operational Protocols

For this study nine to ten week old female C57Bl6 mice are launched on the space shuttle. Flight mice are treated once with a placebo vehicle or therapeutic agent approximately 24 hours before launch. Ground control mice are treated in the same manner but with a 48 hour offset. Ground control mice are housed under the same environmental conditions (temperature, light/dark cycle, humidity, oxygen levels and carbon dioxide levels) as the flight mice. All mice receive the same full access to food and water. Upon return to Earth, the AEMs are returned to the research team for analysis. Body weight is also measured preflight and postflight. Statistical comparisons will be made between the treated and control mice.

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Results/More Information

Cerebral Artery, Mesenteric Vein, Heart, Soleus
Michael D. Delp, Ph.D., University of Florida, Gainesville, FL

Ground based studies in rats subjected to chronic head-down tail suspension have been conducted to simulate the fluid shift towards the head and general cardiovascular deconditioning that occurs with space flight. The purpose of this study was to test the hypothesis, derived from the results of the aforementioned experiments, that 13 days of space flight, aboard the STS-135 mission, would enhance narrowing of the blood vessels, increase the thickness of the innermost layers of the arterial wall and elicit no change in the mechanical properties of mouse cerebral arteries (Taylor 2013).

Contrary to the hypothesis, the results showed that myogenic vasoconstriction was less in cerebral arteries from space flight mice, passive pressure-diameter response indicated greater ability for vascular expansion and contraction and mechanical testing revealed that the arteries from space flight animals had lower effective elastic modulus (tendency to be deformed when force is applied) and stiffness. Gross structural measurements demonstrated that maximal diameter was greater in space flight mice, while medial wall thickness of cerebral arteries was not different between space flight and ground control mice. These results demonstrate that space flight alters vasoconstrictor, mechanical and gross structural properties of cerebral resistance arteries. Collectively, these changes in the functional vasoconstrictor and mechanical properties of cerebral arteries suggest that blood flow to the brain may be elevated during space flight. Although elevated partial pressure of CO₂ in the closed microgravity environment may contribute to alterations in the properties of cerebral arteries, high CO₂ levels alone cannot fully account for such changes. Finally, if similar alterations in the properties of cerebral arteries occur in astronauts, elevations in brain blood flow could serve to elevate intracranial pressure and possibly contribute to the visual impairment reported to occur in astronauts (Taylor 2013).

Cardiovascular adaptations to microgravity undermine the physiologic capacity to respond to challenges related to an upright posture on return to terrestrial gravity. This study investigates the influence of space flight on the constriction of mouse muscle arteries either in response to a stimulus (vasoconstriction) or under their own power (myogenic contraction) and to determine the impacts on bone and muscle mass loss.  Total body mass tended to be lower in space flight animals and muscle mass was 7-13% lower in space flight mice. Space flight was found to decrease vasoconstrictor responses but did not affect the myogenic responsiveness. The thickness of the vessel walls was not found to differ between the two groups. The lack of change in vessel wall thickness suggests that the blood volume redistribution is insignificant in mice during space flight and likely reflects that blood flow to the portion of muscle being tested was preserved. This is an important shortcoming and demonstrates that the mouse may not be an ideal animal model to study this phenomenon. If applicable to the human condition, these results suggest that microgravity-induced changes in the vasoconstrictor characteristics of skeletal muscle resistance arteries could compromise the ability to raise peripheral vascular resistance in order to regulate arterial blood pressure when standing (Stabley 2012).

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Results Publications

Stabley JN, Dominguez JM, Dominguez CE, Mora Solis FR, Ahlgren J, Behnke BJ, Muller-Delp JM, Muller-Delp JM, Delp MD.  Spaceflight Reduces Vasoconstrictor Responsiveness of Skeletal Muscle Resistance Arteries in Mice. Journal of Advanced Materials. 2012 11/01/2012; 113(9): 1439-1445. DOI: 10.1152/japplphysiol.00772.2012.


Taylor CR, Hanna M, Behnke BJ, Stabley JN, McCullough D, Davis, III RT, Ghosh P, Papadopoulos A, Muller-Delp JM, Muller-Delp JM, Delp MD.  Spaceflight-induced alterations in cerebral artery vasoconstrictor, mechanical, and structural properties: implications for elevated cerebral perfusion and intracranial pressure. The FASEB Journal. 2013 March 1; epub. DOI: 10.1096/fj.12-222687.

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Ground Based Results Publications

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ISS Patents

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Related Publications

Converino VA.  Physiological adaptations to weightlessness: effects on exercise and work performance. Exercise and Sport Sciences Reviews. 1990; 18: 119-166.


Tuday EC, Nyhan D, Shoukas AA, Berkowitz DE.  Simulated microgravity-induced aortic remodeling. Journal of Applied Physiology. 2009; 106: 2002-2008.


Morey-Holton ER, Globus RK, Kaplansky AS, Durnova GN.  The hindlimb unloading rat model: literature overview, technique update and comparison with space flight data. Advances in Space Biology and Medicine. 2005; 10: 7-40.


Ma J, Zhang LF, Yu Z, Zhang L.  Time course and reversibility of arterial vasoreactivity changes in simulated microgravity rats. Journal of Gravitational Physiology. 1997; 4: P45-P46.


McDonald KS, Delp MD, Fitts RH.  Effect of hindlimb unweighting on tissue blood flow in the rat. Journal of Applied Physiology. 1992; 72: 2210-2218.


Delp MD, Colleran PN, Wilkerson MK, McCurdy MR, Muller-Delp JM, Muller-Delp JM.  Structural and functional remodeling of skeletal muscle microvasculature is induced by simulated microgravity. American Journal of Physiology: Heart and Circulatory Physiology. 2000; 278: H1866-H1873.


Gashev AA, Delp MD, Zawieja DC.  Inhibition of active lymph pump by simulated microgravity in rats. American Journal of Physiology: Heart and Circulatory Physiology. 2006; 290: H2295-H2308.


Doty SB, Morey-Holton ER, Durnova GN, Kaplansky AS.  Cosmos 1887: morphology, histochemistry and vasculature of the growing rat tibia. Federation of American Societies for Experimental Biology Journal. 1990; 4: 16-23.


Zhang LF, Mao QW, Ma J, Yu Z.  Effects of simulated weightlessness on arterial vasculature (an experimental study of vascular deconditioning). Journal of Gravitational Physiology. 1996; 3: 5-8.


Hargens AR, Steskal J, Johansson C, Tipton CM.  Tissue fluid shift, forelimb loading, and tail tension in tail-suspended rats. The Physiologist. 1984; 27: S37-38.

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Related Websites

Space Biosciences Division

BioServe Space Technology

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Imagery

NASA Image: JSC2011-E029133 - STS-135 crew members, from the right are NASA astronauts Chris Ferguson, commander; Sandy Magnus and Rex Walheim, both mission specialists, participate in an Animal Enclosure Module (AEM) training session in the Jake Garn Simulation and Training Facility at NASA's Johnson Space Center.
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