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MINI REVIEW
published: 29 October 2021
doi: 10.3389/fcell.2021.750775
Microgravity × Radiation: A Space
Mechanobiology Approach Toward
Cardiovascular Function and Disease
Carin Basirun1,2, Melanie L. Ferlazzo2,3, Nicholas R. Howell2, Guo-Jun Liu2,4,
Ryan J. Middleton2, Boris Martinac5, S. Anand Narayanan6, Kate Poole7,
Carmine Gentile1,8 and Joshua Chou1*
1 School of Biomedical Engineering, Faculty of Engineering and Information Technology, University of Technology Sydney,
Sydney, NSW, Australia, 2 Australian Nuclear Science and Technology Organisation, Lucas Heights, NSW, Australia, 3 Inserm,
U1296 Unit, Radiation: Defense, Health and Environment, Centre Léon Bérard, Lyon, France, 4 Discipline of Medical Imaging
and Radiation Sciences, Faculty of Medicine and Health, Brain and Mind Centre, The University of Sydney, Camperdown,
NSW, Australia, 5 Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Sydney, NSW,
Australia, 6 Department of Nutrition and Integrative Physiology, Florida State University, Tallahassee, FL, United States,
7 EMBL Australia Node in Single Molecule Science, Faculty of Medicine, School of Medical Sciences, University of New
South Wales, Sydney, NSW, Australia, 8 Faculty of Medicine and Health, Sydney Medical School, The University of Sydney,
Sydney, NSW, Australia
Edited by:
Claudia Tanja Mierke,
Leipzig University, Germany In recent years, there has been an increasing interest in space exploration, supported
Reviewed by: by the accelerated technological advancements in the field. This has led to a new
Maria A. Mariggiò, potential environment that humans could be exposed to in the very near future, and
University of Studies G. d’Annunzio therefore an increasing request to evaluate the impact this may have on our body,
Chieti and Pescara, Italy
Michele Balsamo, including health risks associated with this endeavor. A critical component in regulating
Kayser Italia S.r.l., Italy the human pathophysiology is represented by the cardiovascular system, which may be
Irina Larina,
Institute of Biomedical Problems heavily affected in these extreme environments of microgravity and radiation. This mini
of Russian Academy of Sciences review aims to identify the impact of microgravity and radiation on the cardiovascular
(RAS), Russia system. Being able to understand the effect that comes with deep space explorations,
*Correspondence: including that of microgravity and space radiation, may also allow us to get a deeper
Joshua Chou
Joshua.chou@uts.edu.au understanding of the heart and ultimately our own basic physiological processes.
This information may unlock new factors to consider with space exploration whilst
Specialty section:
This article was submitted to simultaneously increasing our knowledge of the cardiovascular system and potentially
Cell Adhesion and Migration, associated diseases.
a section of the journal
Frontiers in Cell and Developmental Keywords: mechanobiology, microgravity, cardiovascular, mechanotransduction, cardiac disease, radiation
Biology
Received: 31 July 2021
Accepted: 11 October 2021 INTRODUCTION
Published: 29 October 2021
Citation: Cardiovascular disease (CVD) is one of the leading causes of death in adults in many countries
Basirun C, Ferlazzo ML, (Lozano et al., 2012). Due to the devastating rate of fatality, many researchers have been motivated
Howell NR, Liu G-J, Middleton RJ, to develop clinical models to simulate responses to treatment and drugs to CVD (Gentile, 2016;
Martinac B, Narayanan SA, Poole K, Polonchuk et al., 2017, 2021; Roche et al., 2021; Sharma and Gentile, 2021; Sharma et al., 2021).
Gentile C and Chou J (2021)
Microgravity × Radiation: A Space Abbreviations: CVD, cardiovascular disease; ECM, extracellular matrix; ISS, International Space Station; CPCs, cardiac
Mechanobiology Approach Toward progenitor cells; hiPSC-CMs, human induced pluripotent stem cells; CGR, cosmic galactic rays; SPE, Solar Particle Events;
Cardiovascular Function and Disease. EVA, Extra Vehicular Activities; LET, Linear Energy Transfer; ECs, endothelial cells; DSBs, DNA double strand breaks; YAP,
Front. Cell Dev. Biol. 9:750775. yes-associated protein; TAZ, transcription co-activator; Ca2+, calcium ion; ROS, reactive oxygen species; RPM, random
doi: 10.3389/fcell.2021.750775 positioning machine; RWV, rotating wall vessel.
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Basirun et al. Space Mechanobiology in Cardiac Function
New approach and concept are needed to understand the model have shown a significant elevation of microvascular
complexity of cardiac function and disease onset. Interestingly, pressures in the head, and increased capillary fluid filtration
the effects of spaceflight on the human body appear to mimic (Parazynski et al., 1991; Christ et al., 2001). Short-duration
an accelerated aging process that negatively impacts the heart spaceflight has shown increased capillary fluid filtration, as well;
and the cardiovascular system and closely resembles CVD however, this phenomenon is unknown in the context of long-
(Hughson et al., 2016, 2018). Furthermore, the heart is also duration spaceflight (Leach et al., 1996). These microvascular
known to be sensitive to radiation; therefore, the response and adaptations are related with the fluid redistribution phenomenon
any associated risk and diseases need to be considered when highlighted previously, and in turn, suggest vascular adaptations.
examining the impact of space exploration. As such, a deeper Several ex vivo studies have shown that the structure and function
understanding of the cardiogenic effects of microgravity and of blood vessels certainly adapts to spaceflight, real and simulated,
radiation may have implications for human spaceflight as well as however, there currently exist no in vivo rodent equivalent studies
treat millions of heart disease patients on Earth. As microgravity (Delp, 1999, 2007). There exists a much more thorough literature
and radiation happen simultaneously during space travel, it is of in vivo studies, both of crew and rodent analog models,
of great interest to study the compounding impact on living spaceflight and ground based. Observations from astronauts
matter exposed to microgravity and radiation environment at that have returned from a 6-month spaceflight have shown an
the same time. Due to the complexity of such research, there increase in stiffness in the carotid artery, which is comparable
is still much unknown regarding the effect of spaceflight on to 20 years of aging (Kawasaki et al., 1987; Gepner et al., 2014;
the cardiovascular system. In this mini review, a new approach Hughson et al., 2016). This reduced cardiac function leads to
toward the understanding of cardiac function and disease can be a reduction in tissue mass of the heart, also known as cardiac
found in space mechanobiology. Space mechanobiology can be atrophy, which ultimately causes debilitating changes in heart
defined as the study of how cells are influenced by their physical function. More recent in vivo vascular studies of crew during
environment and in this case by the microgravity environment. long-duration International Space Station (ISS) missions have
To fully understand the function and underlying mechanisms of shown spaceflight-induced structural and functional changes of
cardiac function and the mechanism and markers for CVD, it is the carotid and brachial arteries. From this study, no changes
important to first understand how cardiac cells transduce these in carotid or brachial arteries were generally seen; however, it is
mechanical stimuli. The extracellular matrix (ECM) plays a vital important to note that crew flight studies have a small sample size
part in carrying and providing mechanical cues to these cardiac and variability between crew responses that may influence certain
cells. These mechanical cues are then transformed into biological measures. For indeed in this study, cardiovascular biomarkers
responses (Martino et al., 2018). As the heart is a mechanical of oxidative stress and inflammation (e.g., increased PGF2a,
organ that is highly responsive to different types of mechanical oxidized LDL, TNF-a, myeloperoxidase, etc.) were elevated
stimuli (Takahashi et al., 2013; Guo and Huebsch, 2020), this mini during spaceflight (Lee et al., 2020). Indeed, there are suggestions
review will demonstrate the importance of mechanotransduction that all astronauts more notably the Apollo astronauts that
and how space microgravity and radiation can be leveraged to traveled to the Moon and back had comparatively greater CVD
advance our understanding of cardiac function and disease. risks (Delp et al., 2016).
Although it remains unclear how future exploration missions,
and as a result, extended altered gravity field durations and
THE EFFECT OF MICROGRAVITY ON higher radiation exposures may exacerbate these effects. On-
THE CARDIOVASCULAR SYSTEM going and future studies and further in vivo rodent studies
complemented with ex vivo and in vitro analyses to assess
Exposure to microgravity which differs from the normal state the functional, structural, and biochemical adaptations of
of gravity, puts the human body under critical physiological cardiovascular adaptations to spaceflight can be utilized in the
changes, some of the considerable importance to survival. Gravity field of space mechanobiology for more in-depth study for the
is an important factor of fluid distribution and therefore plays cardiovascular system.
an important factor in the cardiovascular system. Under normal
gravity where the human body is in an upright position, there
is higher arterial pressure (200 mmHg) in the feet and lower
pressure (70 mmHg) in the head. Whereas the heart relative to THE ROLE(S) PLAYED BY
arterial pressure is 100 mmHg. In a microgravity environment MICROGRAVITY ON CARDIOMYOCYTE
this fluid distribution is altered, losing the gradient and the FUNCTION
fluid distribution becomes more uniform throughout the body
(Hargens and Richardson, 2009; Demontis et al., 2017). This, Spaceflight exposure also leads to various cellular and organ
in turn, reduces the demand for arterial blood pressure and adaptations, though the in vivo study of cardiovascular
decreases the amount of work the heart has to do leading to adaptations, whether through actual and/or ground simulated
cardiovascular deconditioning and increased risk of CVD. studies, is limited. Several studies have looked at the impact
Head-down tilt is one ground-based analog model for of microgravity on cell proliferation and differentiation. These
studying simulated microgravity and therefore cardiovascular studies have demonstrated that stem cells that were grown in
deconditioning effects, where previous reports utilizing this a microgravity environment grow differently from those grown
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Basirun et al. Space Mechanobiology in Cardiac Function
under normal gravity, showing changes in division, contraction, creating high Linear Energy Transfer (LET) but low energy
and migration (Zhang et al., 2015; Shinde et al., 2016). metallic particles and protons. The inside of the vessel is also
Recent studies that involved the cells of the cardiovascular subjected to a higher constant low dose of gamma radiation,
system looked at cardiac progenitor cells (CPCs) cultured on about twice the highest natural radiation background found on
the ISS. Alterations to transcriptional control were measured Earth (Restier-Verlet et al., 2021).
and it was found that among both neonatal and adult CPCs, When discussing radiation, we measure the “activity” of
the significantly dysregulated microRNAs affect cytoskeletal radiation where we measure how much radiation is coming
remodeling and mechanotransduction pathways. Genes out of something and “exposure” to radiation that measure the
related to mechanotransduction were downregulated, while effect of radiation that has been absorbed by the substance.
the expression of cytoskeletal genes and calcium signaling Radiation exposure is measured in gray (Gy), and this allows for
molecules was significantly elevated only in neonatal CPCs. a common unit of measurement of different types of radiation
Cytoskeletal organization and migration were both affected by by measuring their effect on materials. Since not all radiation
spaceflight in neonatal and adult CPCs, however, only neonatal has the same effect biologically, we use sieverts (Sv) to measure
CPCs experienced increased expression of early developmental the absorbed dose in human tissue to the biological damage to
markers and a higher potential to proliferate (Baio et al., 2018; radiation (Australian Radiation Protection and Nuclear Safety
Camberos et al., 2019, 2021). Agency [ARPANSA], n.d.). The radiation doses received for
Wnorowski et al. (2019) have shown that monolayers space explorers depend on the time and distance from earth.
of beating cardiomyocytes derived from human induced Estimated doses are 150 mSv/year for space flight in the ISS,
pluripotent stem cells (hiPSC-CMs) that were sent to the ISS 300–400 mSv for traveling to the Moon, and 300–400 mSv/year
for a period of 5.5 weeks, had no significant effect on the and 1600–2300 mSv for 2 years traveling to Mars (Shavers
morphology. Looking at functional differences between the et al., 2004; Chancellor et al., 2018; Restier-Verlet et al., 2021)
two samples, there were no significant difference in velocity in higher doses of radiation (>100 mGy) it has been clinically
during contraction and relaxation. However, some functional shown to lead to cardiac dysfunction over time, where cases
differences were observed, where the space-flown hiPSC-CMs have been reported following radiotherapy. Short and long-
had a decreased calcium recycling rate as well as an observed term effects of radiation induced cardiovascular diseases were
beating irregularity when the samples were assessed following observed following radiotherapy treatment of cancers adjacent
their return to Earth. These results suggested that following the to heart including lungs, breasts, and esophagus. The hearts
samples return to normal gravity, their calcium-handling-related of patients received 1.6–3.9 Gy radiation during radiotherapy
parameters remained altered (Wnorowski et al., 2019). treatment of peptic ulcer disease increased risk of coronary
Although Baio et al. (2018) and Wnorowski et al. (2019) had heart disease (Carr et al., 2005). In breast cancer radiotherapy,
similar microgravity conditions with the samples flown to the ISS, women’s hearts received doses 2.7–6.3 Gy which significantly
there were discrepancies in results including the contradiction in increased risk of developing ischemic heart disease (McGale
the expression of DNA repair genes and this may be attributed et al., 2011). Hughson et al. (2016) studies have suggested that
by several experimental conditions, one of them being that the astronauts spending 6 months in spaceflight increased stiffness
type of cells used by Baio et al. (2018) being progenitor cells of carotid artery and insulin resistance. The increase stiffness
and Wnorowski et al. (2019) used differentiated cardiomyocytes. of carotid artery and insulin resistance may cause by multiple
There are other experimental conditions that can be considered and compounding factors including radiation and microgravity.
between these and other experiments in the field, including the In a rat model Soucy et al. (2011) have demonstrated the
duration of exposure to microgravity and the way the cells were detrimental effects of ionizing radiation. The rats exposed 1 Gy
processed for the assays. Other studies including different cell high-energy iron-ion radiation at approximately 0.5 Gy/min
types in the cardiovascular response to simulated microgravity exhibit higher aortic stiffness and a greater level of endothelial
is summarized in Table 1A and the response to spaceflight dysfunction 4 months post radiation. This mainly involves
microgravity is summarized in Table 1B. increased oxidative stress as well as inflammation, playing a
role in radiation-induced cardiovascular damage, which has
been highlighted by multiple studies (Soucy et al., 2011;
THE EFFECT OF RADIATION ON THE Coleman et al., 2015; Seawright et al., 2017; Table 1C). The
CARDIOVASCULAR SYSTEM relationship between dosage and response for some biological
effects are therefore not linear and not proportional to dose
Space radiation consists of solar and cosmic galactic rays (CGR) (Betlazar et al., 2016, 2020, 2021; Puukila et al., 2017; Tang and
mainly composed of respectively, low and high energy protons, Loganovsky, 2018). Chronic low doses of radiation (<100 mGy)
alpha particles and a minority of heavy charged particles and may not be detrimental and could even induce benefits to
nuclei. Solar Particle Events (SPE) are temporary phenomena that the central nervous system and possibly to the cardiovascular
increase the flux of protons. Astronauts are exposed to these solar system. However, it is unknown what impact of primarily low-
and cosmic components only during Extra Vehicular Activities dose rate radiation will have on the cardiovascular system
(EVA) and most of the times they remain inside their spacecraft during space exploration (Boerma et al., 2016), particularly in
or the ISS, where SPE could still be considered. Another source the presence of compounding factors including microgravity.
of radiation is the interaction of solar and CGR with shielding, Therefore, the study by combing compounding factors radiation
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TABLE 1 | Summary of cardiovascular responses to microgravity and radiation.
(A) Microgravity-induced cardiovascular response
Cell origin µG simulation method Findings References
Human pluripotent stem Random positioning machine (RPM) - Production of highly viable and enriched cardiomyocytes
cells (hPSCs) - Promote the induction of cardiac progenitors, CM differentiation, Jha et al., 2016
proliferation and
- increase cell survival of cardiac progenitors
Endothelial cells Random positioning machine - Increase in ECM proteins and altered cytoskeletal components and
(EA.hy926) (RPM) intermediate filaments Infanger et al.,
2006
- Induced apoptosis in endothelial cells
- Formation of 3D cell aggregates; assembly to tube like structures
Human pulmonary 3D clinostat - Tight junctions between cells were absent Kang et al.,
microvascular endothelial - Apoptosis positive cells are extensively shown 2011
cells (HPMECs)
- Disorganized and depolymerized, extenuated actin filaments
Heart cells from 2–4-day Rotating bioreactor - Rat heart cells-based construct observed spontaneous and synchronous Freed and
old rats and 15-day old contraction Vunjak-
chick embryos - Highest fraction of total regenerated tissue mass Novakovic,
1997
HL-1 cardiomyocytes 2D clinostat - Increased concentrations of cytosolic calcium and spontaneous calcium
oscillations
- Induced cardiomyocyte atrophy Liu et al., 2020
- Decreased cell size
Primary rat neonatal Rotating wall vessel (RWV) - Decreased protein turnover
cardiomyocytes (NRCM) - Unaffected apoptosis, cell viability and protein degradation
- Upregulation of protein content and processes in mitochondrial protein translation Feger et al.,
- Downregulation in proteins and protein translation in the rough endoplasmic 2016
reticulum and ribosomes
Adult and neonatal 2D clinostat - Age dependent responses tube formation Fuentes et al.,
cardiac progenitor cells - Increase in growth factor expression 2015
(Isl-1 + CPCs) - Elevated expression of stemness associated genes in neonatal CPCs
- Elevated transcription of DNA repair genes in neonatal CPCs
Endothelial cells Random positioning machine - Formation of tube-like structure with walls of single-layered ECs Grimm et al.,
(EA.hy926) (RPM) 2009
(B) Effect of microgravity and radiation on cardiovascular system cells
in vitro
Cell origin Space µG/µG Space radiation/ Findings References
simulation method radiation source
Human induced Space Space - Decreased calcium recycling rate as well as an observed beating Wnorowski
pluripotent stem cells – µG (ISS) radiation (ISS) irregularity et al., 2019
derived cardiomyocytes - Significant upregulation of sarcomere genes
(hiPSC-CMs) - Significant decrease in DNA damage and repair genes
- 2,635 genes were differentially expressed among flight, post-flight,
and ground control samples
Adult cardiac progenitor Space Space - Upregulation of YAP1 expression Camberos
cells (CPCs) µG (ISS)/ radiation - Short term YAP1 activation et al., 2019
Simulated µG (ISS)
(2D clinostat)
Neonatal and adult Space Space - Mechanotransduction genes are downregulated in neonatal CPCs Baio et al.,
human cardiac progenitor µG (ISS) radiation (ISS) and upregulated in adult CPCs 2018
cells (CPCs) - Increased expression of early developmental markers and enhanced
proliferative potential in neonatal CPCs
- Increased expression of DNA repair genes in both adult and neonatal CPCs
Adult and neonatal Space Space - Transcript associated with stemness is significantly elevated Camberos
cardiac progenitor cells µG (ISS) radiation (ISS) - Key transcripts involved in cell cycle progression, cell differentiation, et al., 2021
(CPCs) heart development, oxidative stress and focal adhesion were induced
(Continued)
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TABLE 1 | (Continued)
(C) Radiation-induced cardiovascular response
Cell origin Radiation source Findings References
Wistar (Harlan) male rats HZE 56Fe-ion (0, 0.5, or 1 Gy) - In vivo aortic stiffness
- Significantly higher ROS production Soucy et al.,
2011
Human umbilical vein Iron-ion or proton (1 Gy) - Inhibition of vessel formation Grabham et al.,
cells (HUVEC) 2013
C57BL/6J mice Proton (0.1 Gy) or heavy iron ions - Alternations in the methylation and expression of DNA repetitive Koturbash
(0.5 Gy) elements in cardiac tissues et al., 2016
and microgravity is crucial to examine the impact of space observed that DNA damage and repair genes were significantly
exploration on the cardiovascular system. decreased in the flight samples when compared to the post-
Microgravity and space radiation are unique and extreme flight and ground samples. This is different to the observation
environments which have been demonstrated to induce or model from the study by Baio et al. (2018) where both the neonatal
onsets of cardiovascular diseases and therefore has the potential and adult CPCs showed increased expression of DNA repair
to elucidate the underlying mechanisms of cardiovascular genes, whilst in a study utilizing simulated microgravity on the
biology. By using microgravity and radiation as “tools” we ground, there is only increased expression of DNA repair genes
could increase our understanding in the mechanotransduction, in neonatal CPCs (Fuentes et al., 2015; Wnorowski et al., 2019).
function and mechanisms of the cardiovascular system and As results from ground simulated microgravity and spaceflight
subsequently the on-set of diseases. microgravity studies and the effect it has on the cardiovascular
system has been conflicting there may be other factors to
consider, one of them being the level of radiation that will be
IS IT MICROGRAVITY OR RADIATION, considerably higher aboard the ISS than on Earth (Moreno-
OR BOTH? Villanueva et al., 2017; Wnorowski et al., 2019). The difference
in the level of radiation may impact the cell’s response aboard in-
The majority of studies have focused on utilizing stem cells and flight and on the ground. Molecularly, radiation and microgravity
looking into their development (Table 1B). There are currently have been shown to have a negative impact on the integrity of
limited studies that have explored the effects of both microgravity DNA. To prevent DNA damage, cells have developed specific
and space radiation as a mechanism for CVD-causing processes. mechanisms that allow them to locate and repair DNA lesions.
Both microgravity and space radiation, separately, have been Usually, cells can withstand a moderate level of DNA damage
shown to exhibit significant changes at both subcellular and with the help of these repair processes; however, the lack of
tissue levels; however, exploring the effects of the two stressors gravity may unfavorably affect this process that tries and prevent
in combination would be beneficial to our understanding of the the DNA damage, leading to the accumulation of DNA miss-
space environment. matched repair (Moreno-Villanueva et al., 2017).
Endothelial cells (ECs) have been observed to form tube-
like aggregates during both spaceflight and simulated gravity,
confirming the influence of microgravity for 3D aggregation of CARDIAC MECHANOTRANSDUCTION
ECs with and without the influence of radiation (Krüger et al.,
2019). Tan et al. (2020) looked at human bronchial epithelial Previously mentioned study by Hughson et al. (2016)
Beas-2B cells under simulated microgravity for 48 h followed by suggested that microgravity and radiation cause an increase
X-ray radiation. Although this is not specific to the cardiovascular in stiffness in carotid artery. The carotid artery stiffness
system, the results were interesting in that the effects were was compared between pre- and postflight; it was seen
shown to be additive. This study showed that the simulated that the stiffness was significantly increased postflight.
microgravity on its own significantly reduced the survival of Studies have shown that under normal gravity condition
the cells and with the addition of radiation (1–6 Gy) it further this increase in stiffness happens with the increase in age.
inhibited cell survival -and cell proliferation (Tan et al., 2020). However, this increase in stiffness could already be seen
It is also well known that DNA double-strand breaks (DSBs) in the participants of the study as a result of the space
are a prominent consequence of radiation exposure, forming condition (Hughson et al., 2016). Animal model further
γH2AX foci as an early cellular response to DSBs (Sedelnikova confirmed that space environment contributes to higher
et al., 2007; Mah et al., 2010). In this study, it was observed aortic stiffness, where rats exposed to high energy radiation
that the compound effect of simulated microgravity and radiation that simulated the space environment also have significantly
significantly promoted the formation of γH2AX foci compared higher aortic stiffness over a 6-month period (Soucy et al.,
to independent exposure of the two factors (Tan et al., 2020). 2011). Although the mechanism for the change is different
Looking into studies done on the ISS, Wnorowski et al. (2019) between spaceflight and aging, the magnitude of change is
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FIGURE 1 | A space mechanobiology approach toward cardiovascular function and disease.
significant. Arterial stiffness has also been believed to be The Yes-associated protein (YAP) and its paralog TAZ
a precursor to atherosclerosis and a marker for increased (transcription co-activator) have been demonstrated as
cardiovascular disease risk such as myocardial infarction major regulators of cardiac cell survival, proliferation, and
(O’Rourke, 1995; Safar et al., 2003; Zieman et al., 2005). differentiation (Xin et al., 2011; von Gise et al., 2012; Lin et al.,
The majority of upregulated proteins in the aortic wall 2014). It has been found that activation of YAP improves
are involved in the actin cytoskeleton organization and by cardiac regeneration (Xin et al., 2013). Furthermore, when
identifying the exact molecular mechanism and mechanical cardiomyocyte-specific activated YAP is overexpressed, there
regulators associated with arterial stiffness, it can aid in is an increase in the proliferation of cardiomyocytes which
identifying therapeutic intervention (Miotto et al., 2021). leads to a cardiac overgrowth in neonatal mice (Xin et al.,
Interestingly, the increased stiffness in the carotid artery 2011). In supporting this, it has been found that YAP protein
that is normally seen in the aging cardiovascular system in can be detected in neonatal hearts; however, with age, the
the population can be simulated by spaceflight (Kawasaki expression decreases, while the phosphorylation of YAP
et al., 1987; Lakatta and Levy, 2003; Gepner et al., 2014; increases with age (von Gise et al., 2012). However, nuclear
Hughson et al., 2016). This process can be utilized in the YAP expression that is usually missing in adult cardiomyocytes
field of space mechanobiology for more in-depth study of the shows in infarcted cardiac tissue at the border of the infarcted
mechanotransduction responses in the cardiovascular system in region. The reason for this could be a result of the increased
relation to cardiovascular diseases. stiffness in the ECM that is exhibited in the infarcted area
There are a number of proteins that are sensitive and (Mosqueira et al., 2014). Interestingly, both spaceflight and
responsive to changes in the mechanical environment and simulated microgravity has been shown to upregulate YAP1
looking at these key proteins could elucidate the relationship expression in adult CPCs and downregulation in neonatal
between cell function and their responses to these mechanical CPCs (Baio et al., 2018; Camberos et al., 2019). This indicates
cues. By looking at the expressions of these proteins, it can then that microgravity can induce functions and responses to
be used as a measure of mechanotransduction (Chin et al., 2019). damage on the heart.
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Another key cardiac mechanotransducer associated with biologists in investigating this interface of cell biology and
the mechanical stretching of cardiac tissues is Piezo1, biomedical engineering.
which is a membrane mechanosensor. Activation of A key element that was not discussed in this mini review
Piezo1 occurs due to the vascular shear stress in the is the technologies to conduct microgravity and/or simulated
human body, which is derived through the effects of microgravity research but there are clear advancements in this
heart contraction (Beech and Kalli, 2019). Recently it has area made available for researchers. Whilst there have been
been shown that Piezo1 in cardiomyocytes is triggered several studies in space on the cardiac responses and genetic
by cell stretching (Guo et al., 2020), which indicates that and epigenetic profiling on the effects of microgravity, this sets
Piezo1 plays a vital part as an ion channel contributing the foundation and the stage to examine the underlying cellular
to the feedback of the mechano-electric response of the mechanisms of the cardiovascular system. More comparison
cardiac cells utilizing its Ca2+ transient control during between experiments on Earth and ISS needs to be done
cardiac cell stretching. Another study confirmed that the to validate the simulations done on the ground and open
Piezo1 channel directly converts the mechanical stretch more doors to research that simulate the space conditions
of cardiomyocytes into calcium ion (Ca2+) and reactive which will allow us to look into space mechanobiology with
oxygen species (ROS) signaling, and when Piezo1 is greater control. Furthermore, as demonstrated in this mini
overexpressed or deleted, it resulted in heart dysfunction review, the majority of research shown on cardiac cells
(Jiang et al., 2021). have been done on microgravity and radiation independently;
It is evident that mechanotransduction in the form of however, there are limited studies that combine these two
mechanical cues, ECM and mechanical load in the form of gravity external stressors on cells of cardiovascular origin. It is
plays a pivotal role in cardiac homeostasis beyond just YAP and also important to note that the effects of microgravity and
PIEZO. The current gap lies in the fundamental drivers of these radiation has been varied depending on factors such as cell
functions and mechanisms remains unresolved. type, specific bioreactor/cultured environment used and the
type of exposure.
The unwavering question of whether microgravity or radiation
DISCUSSION or the dual effects have on cardiac function remains open
for discovery and ultimately both of these conditions are a
The human heart is a vital organ that pumps blood throughout new type of extreme environment in which researchers can
the body using the circulatory system to supply nutrients and uncover knowledge from cellular to organ level. As shown in
remove waste from the tissues. As it is a vital part of the human this mini review, there is still a great amount of unknown to
body, it is important that the issue of cardiovascular health the underlying mechanisms of cardiac function and CVD onsets,
and diseases are understood and addressed. The complexity of and whilst there exist several novel and innovative approaches
the cellular anatomy of the human heart makes it challenging toward advancing this understanding, gap in knowledge remains.
to develop a clinically relevant model. Therefore, future The research outlined in this mini review provides a glimpse
effort to address this could include the use of novel in vitro into what can be achieved through microgravity research in
models, including organs on a chip to mature cells (Chen advancing cardiac knowledge and with current CVD death toll
et al., 2013; Ren et al., 2013; Sharma et al., 2021). Even with still remaining high, it may be time to take an out of this world
an established in vitro and/or in vivo model, to initiate the approach toward CVD.
onset of CVD conditions remains a challenge. As outlined
in this mini review, cardiac mechanotransduction plays an
important role in not only understanding the cardiovascular AUTHOR CONTRIBUTIONS
system, but also in the maturation and the functional response
of the cardiac tissue. It has been demonstrated in studies CB wrote the manuscript. SN contributed to the section “The
how cardiac mechanosensing regulators including YAP and Effect of Microgravity on the Cardiovascular System.” MF, G-JL,
PIEZO1 regulate cardiac tissue function and dysfunction, RM, and NH contributed to the section “The Effect of Radiation
including cardiac cell survival, proliferation, differentiation on the Cardiovascular System.” CG, BM, KP, and JC initiated,
and responses to mechanical stimuli (Xin et al., 2011; von conceptualized the review, and edited the manuscript. All authors
Gise et al., 2012; Lin et al., 2014; Beech and Kalli, 2019; have read and agreed to the published version of the manuscript.
Guo et al., 2020; Jiang et al., 2021). The main effects of
microgravity and radiation on the cardiovascular system
has been demonstrated to show changes can be seen from a FUNDING
physiological to a cellular level, including changes to cardiac
and endothelial function, increased stiffness of carotid artery, The author acknowledges the support of the Australian Research
oxidative stress and inflammation as well as altered fluid Council Discovery Project (ARC DP) [DP190101973 to JC,
distribution and decreased calcium recycling rate. As further the support of The University of Sydney (Cardiothoracic
highlighted in this mini-review the complexity and cross-talk Surgery Research Grant)], UTS (Seed Funding), and Catholic
between different mechanosensors and regulators remain Archdiocese of Sydney (Grant for Adult Stem Cell Research), Ian
elusive and reinforce the opportunities for cardiac and space Potter Foundation Grant to CG.
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ACKNOWLEDGMENTS Residential Student Scholarship 2020 to CB) to enable
work on this research. MF received the support of
We would like to acknowledge Australian Government Centre National d’etudes Spatiales (CNES). Figure 1 was
Research Training Program Scholarship and AINSE provided by ©Chelsea Ly including illustrations from
Limited for providing financial assistance (Award – BioRender.com.
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Cardiomyocyte Structure and Function. Stem Cell Rep. 13, 960–969. doi: 10. Conflict of Interest: The authors declare that the research was conducted in the
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Xin, M., Kim, Y., Sutherland, L. B., Murakami, M., Qi, X., McAnally, J., et al. (2013). potential conflict of interest.
Hippo pathway effector Yap promotes cardiac regeneration. Proc. Natl. Acad.
Sci. U. S. A. 110, 13839–13844. doi: 10.1073/pnas.1313192110 Publisher’s Note: All claims expressed in this article are solely those of the authors
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