Poster H13 - The Effect of Simulated Microgravity and Radiation on Large Artery Stiffness in Mice

Saturday, October 26, 2024

10:00 AM - 11:00 AM EST

Location: Exhibit Hall E, F & G

Presenting Author(s)

MM

Malia R. Mason, n/a

Undergraguate Researcher
Department of Biomedical Engineering, University of Utah College of Engineering; Geriatric Research Education and Clinical Center, Veteran’s Affairs Medical Center - Salt Lake City, Salt Lake City, UT
South Salt Lake, Utah, United States

Co-Author(s)

DM

Denisse G. Moreno, Medical degree

Postdoctoral Fellow
Geriatric Research Education and Clinical Center, Veteran’s Affairs Medical Center - Salt Lake City, Salt Lake City, UT; Division of Geriatrics, Division of Cardiology, Department of Internal Medicine, University of Utah School of Medicine, United States

Last Author(s)

MB

Marjan Boerma, PhD

Professor
College of Pharmacy, University of Arkansas for Medical Sciences, United States

Primary Investigator(s)

ET

Eric Tuday, M.D., Ph.D.

Assistant Professor
Geriatric Research Education and Clinical Center, Veteran’s Affairs Medical Center - Salt Lake City, Salt Lake City, UT; Division of Geriatrics, Division of Cardiology, Department of Internal Medicine, University of Utah School of Medicine, United States

Introduction: Astronauts often return from the extraterrestrial environment, after experiencing atypical exposures such as microgravity and increased radiation, with altered biologic physiology. Observations have been made that some of these physiologic changes bear some similarities to that of the aging of the cardiovascular system, in particular the development of large artery stiffness (LAS). The development of LAS is multifactorial and includes modifications within the extracellular matrix, increased inflammation, and endothelial/smooth muscle cell dysfunction that can lead to hypertension, heart failure, and other end-organ dysfunction. Cellular senescence is characterized as a state of proliferative arrest, and a change of the cellular phenotype to a non-functional, pro-inflammatory, and pro-fibrotic state which has been shown to contribute to the development of LAS. Recent evidence suggests that exposure to the conditions of spaceflight, microgravity, and galactic cosmic radiation have the potential to induce cellular senescence and lead to premature vascular aging and LAS. Therefore, we aim to demonstrate the effects of interventions designed to mimic the hazards of spaceflight on the development of cellular senescence and examine their correlation to aortic stiffness.

Materials and

Methods: This study utilizes mouse models exposed to different environmental variables associated with spaceflight: a combination of simulated microgravity (hindlimb unloading (HLU)) and simulated exposure to galactic cosmic radiation (5 ion radiation (IR)). A cohort of mice were split into five groups: sham control (Sham), radiation dosed at 0.5 Gy (IR 0.5), hindlimb unloading (HLU), 0.5 Gy radiation in combination with HLU (HLU + IR 0.5), and 1.5 Gy radiation in combination with HLU (HLU + IR 1.5). The aorta of each mouse was dissected and sectioned. Aortic tissue was used to perform quantitative PCR (qPCR) to analyze gene expression of various SASP factors and senescence markers. Aortic rings were used to examine intrinsic stiffness by measuring the forces and stress-strain relationship resulting from stretching until failure using a myograph device.

Results, Conclusions, and Discussions: Results/

Conclusions:
An increase in aortic intrinsic mechanical wall stiffness was observed in samples obtained from mice subjected to the combined interventions of radiation and hindlimb unloading when compared to the Sham group. The HLU group’s elastic modulus trended towards an increase compared to Sham (3541±258.4 vs 2019±116.8, p< 0.05). The HLU + IR 0.5 aortic rings had a greater elastic modulus compared to the Sham control group (5120±822.6 kPA vs 2019±116.8 kPA, p=0.0305, n=4),while HLU + IR 1.5 aortic rings showed the greatest difference from the Sham samples (6437±1021 kPA, p=0.0023, n=4). There was no significant difference observed between the lower and higher dose radiation combined groups (p=0.6062). A complete cellular senescence profile was performed for each group using known senescence markers. Early evidence of senescence was found as indicated by increased relative expression of p16 in the HLU + IR 0.5 and HLU + IR 1.5 aortic tissue. The combined exposures of HLU + IR 1.5 showed the greatest increase in p16 expression (2.992±0.4660), yielding a significant difference from the sham control (1±0.4884, p=0.0110) and individual exposure groups, HLU (0.8876±0.4307, p=0.0048) and IR 0.5 (1.036±0.3746, p=0.0075).

Conclusions:
Our current data suggests that there is development of cellular senescence within the aorta upon exposure to simulated spaceflight in mice. While hindlimb unloading by itself resulted in aortic stiffening, the combined exposure of simulated microgravity and radiation caused the most significant increase in aortic stiffness and senescent markers. These results suggest that the compounded hazards of spaceflight can potentially provoke premature vascular aging and the development of significant large artery stiffness.

Acknowledgements (Optional):