Vascular Health in Space: MicroRNAs in Microgravity (Taylor Vascular) - 08.23.18

Overview | Description | Applications | Operations | Results | Publications | Imagery

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Science Objectives for Everyone
Vascular Health in Space: MicroRNAs in Microgravity (Taylor Vascular) uses mice to evaluate the effects of gravity on the response of microRNA (miRNA) to blood vessel (vascular) injury, and the efficiency of vascular repair in space. Several previous animal and human studies identified changes in heart rates during spaceflight, and miRNAs are known to modulate cardiovascular processes. This study can shed light on how microgravity changes individual cells and tissues, including heart, and how miRNAs relevant to vascular health respond and adapt to spaceflight.
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Information Pending

The following content was provided by Dennis Leveson-Gower, and is maintained in a database by the ISS Program Science Office.
Experiment Details

OpNom:

Principal Investigator(s)
Doris Taylor, Ph.D., FACC, FAHA, Texas Heart Institute, Houston, TX, United States

Co-Investigator(s)/Collaborator(s)
Sonja Schrepfer, M.D., Ph.D., UCSF School of Medicine, San Francisco, CA, United States

Developer(s)
NASA Ames Research Center, Moffett Field, CA, United States
Leidos, Webster, TX, United States

Sponsoring Space Agency
National Aeronautics and Space Administration (NASA)

Sponsoring Organization
NASA Research Office - Space Life and Physical Sciences (NASA Research-SLPS)

Research Benefits
Information Pending

ISS Expedition Duration
-

Expeditions Assigned
57/58

Previous Missions
Information Pending

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Experiment Description

Research Overview

  • The Vascular Health in Space: MicroRNAs in Microgravity (Taylor Vascular) investigation documents the subcellular effects of microgravity. The investigators hypothesize that microRNAs (miRNAs), because of their regulatory function, are involved.
  • miRNAs are now understood to be powerful modulators of biological pathways and have generated considerable excitement as next-generation therapeutic targets for a variety of diseases, including cardiovascular diseases.
  • The gravitational impact on the miRNA response to vascular injury is assessed and the efficiency of vascular repair in space is to be evaluated.
  • The objectives of this study are:
    • To investigate the effect of microgravity on vascular remodeling- associated miRNAs.
    • To investigate the effect of microgravity on miRNAs in healthy vessels.
    • To assess the effect of microgravity on smooth muscle cell Chromosomes (SMC) function in both healthy and diseased vessels.
    • To assess the effect of microgravity on endothelial cells (ECs) and endothelial progenitor cells (EPCs), and on angiogenesis.
  • These experiments can provide new knowledge about how miRNAs relevant to vascular health respond, and adapt, to spaceflight conditions.
  • This data can translate into new therapeutic options to counteract vascular lesions, and restore vascular physiology in microgravity.
  • The understanding of the complex interplay of vascular miRNAs in microgravity has important implications for the maintenance of cardiovascular health in space.

Description

Astronauts are faced with several health risks during both short- and long-duration spaceflight due to the space environment. Microgravity itself seems to affect cardiovascular parameters. For example, studies on animals (rats and rhesus monkeys) have found consistent decreases in heart rate during spaceflight. Similarly, data from 12 astronauts over 6 missions showed that the heart rates of astronauts were reduced in space. These early studies demonstrate an obvious change in an easy to measure cardiovascular parameter.
 
More in-depth studies are required to shed light on how microgravity exerts changes on individual cells and tissues.
 
The Research team believes that subcellular effects of microgravity can be documented and it is hypothesized that microRNAs (miRNAs), because of their regulatory function, are involved. miRNAs are now understood to be powerful modulators of biological pathways, and have generated considerable excitement as next-generation therapeutic targets for a variety of diseases, including cardiovascular diseases.
 
In this investigation, the Research team assesses the gravitational impact on the miRNA response to vascular injury, and evaluates the efficiency of vascular repair in space. This provides further information on how microgravity alters vascular remodeling and healing, and could reveal currently unknown targets for potential therapeutic modulation.
 
The main objectives of Vascular Health in Space: MicroRNAs in Microgravity (Taylor Vascular) are to evaluate the role of miRNAs in vascular disease (Objective 1), vascular health (Objective 2), vascular smooth muscle cell function (Objective 3), and angiogenesis (Objective 4).
 
Previously, the team studied miRNA regulation in diseased human vessels with myointimal lesions, and demonstrated the important regulatory role of miRNAs in vessel injury. Studies demonstrated that various vascular miRNAs were downregulated after vessel injury, and only a few were upregulated. Recent spaceflight studies showed that the expression of miRNAs in both humans and mice were sensitive to gravity. The limited data available demonstrated down-regulation of multiple miRNAs in microgravity. The team has also previously shown that vascular remodeling differs in females and males.
 
Therefore, it is hypothesized that microgravity could aggravate pathologic vessel remodeling via miRNA alterations. Because inflammation is a known stimulus for myointimal hyperplasia, special attention is given to the inflammatory responses to vessel injury.
  • Objective 1 investigates how vascular miRNAs are differentially regulated at normal Earth gravity (1g) and microgravity (μg) in response to vascular balloon injury.
  • Objective 2 investigates the effect of microgravity on miRNAs in healthy vessels. If the gravitational effect on vascular miRNAs is profound, microgravity might even induce the development of vascular lesions in healthy vessels.
  • Objective 3 assesses the effect of microgravity on smooth muscle cell (SMC) function in both healthy and diseased vessels. Under normal physiologic conditions, SMCs rarely proliferate. However, in the presence of injury or a growth stimulus, SMCs begin to proliferate and migrate. Microgravity could be another so far unknown growth stimulus. Uncontrolled SMC proliferation can result in pathologic vasoconstriction, or in myointimal hyperplasia, with narrowing of the lumen or other adverse remodeling. Microgravity might thus affect SMC plasticity.
  • Objective 4 assesses and compares angiogenesis at 1g and microgravity, and defines the role of angiogenetic miRNAs. Since angiogenesis plays an important role in vascular health, it is anticipated that effects of microgravity on angiogenesis-associated miRNAs can impact vascular health and repair processes.

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Applications

Space Applications
Better understanding of how miRNAs relevant to vascular health respond and adapt during spaceflight can translate into therapies to counteract vascular damage, a significant component of heart attacks, and cardiovascular and peripheral vascular disease that decrease blood supply in microgravity. This understanding has important implications for maintaining astronaut cardiovascular health on long-term missions.

Earth Applications
This investigation advances research on vascular miRNAs on Earth, including the possibility of altering miRNA expression in injured vessels using systemic or local delivery of anti-miRNAs. Results could provide insights into genetic regulation and signaling pathways and reveal new targets for therapies, including potential new pharmaceuticals. Cardiovascular disease and peripheral vascular disease are major contributors to morbidity and mortality in the United States.

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Operations

Operational Requirements and Protocols

Female, C57BL/6 mice (6-8 weeks old) are used for this experiment, with 20 being subjected to microgravity, and 20 remaining on earth at 1g controls. The animals remain on the International Space Station for approximately 30 days before being returned to earth alive to the Principal Investigator.
 
Preflight procedures are as follows:
  • Inducing vessel injury in mice before spaceflight (Objective 1). In all mice, the development of myointimal hyperplasia in the abdominal aorta is induced by balloon angioplasty using the model that was established by the Research team. In brief, the abdominal aortic segment of C57Bl6 mice is mechanically injured using a 1.25x13 mm balloon angioplasty catheter. After in situ endothelial removal and vessel overstretch, the balloon catheter is removed. Myointimal hyperplasia develops within 28 to 38 days. This surgery is performed using a microscope under inhalation anesthesia with isoflurane (2%). After surgery, the animals also receive a Matrigel plug s.c. into their right flank (see description below).
  • Implanting the in vivo Matrigel plug in mice before spaceflight (Objective 4). To understand the full regulation of angiogenesis, 500 μl Matrigel is injected s.c. in all 40 animals. Subsequently, a small (0.5 cm) nick is made in the skin and Matrigel using a surgical blade. A sterilized polyvinyl sponge containing 50 ng fibroblast growth factor (FGF) to induce angiogenesis is introduced through the nick in the Matrigel and advanced to the center of the plug followed by skin closure by 1 stitch.
  • All animals receive 5 mg/kg Carprofen s.c. after the procedure and Metamizol to the drinking water (50 mg Metamizol per 100 ml) for pain control for 24 hours post-surgery.

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Decadal Survey Recommendations

Information Pending

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Results/More Information

Information Pending

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Related Websites

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Imagery