From Cultured Vascular Cells to Vessels: The Cellular and Molecular Basis of Vascular Dysfunction in Space

Abstract

Life evolved on this planet under the pull of gravity, shielded from radiation by the magnetosphere and shaped by circadian rhythms due to Earth's rotation on its axis. Once living beings leave such a protective environment, adaptive responses are activated to grant survival. In view of long manned mission out of Earth's orbit, it is relevant to understand how humans adapt to space and if the responses activated might reveal detrimental in the long run. Here we review present knowledge about the effects on the vessels of various extraterrestrial factors on humans as well as in vivo and in vitro experimental models. It emerges that the vasculature activates complex adaptive responses finalized to supply oxygen and nutrients to all the tissues and to remove metabolic waste and carbon dioxide. Most studies point to oxidative stress and mitochondrial dysfunction as mediators of vascular alterations in space. Unraveling the cellular and molecular mechanisms involved in these adaptive processes might offer hints to design proper and personalized countermeasures to predict a safe future in space.

Keywords: endothelial cells; microgravity; spaceflight; vascular smooth muscle cells; vessel.

FIGURE 1

Role of circadian rhythm dysregulation on the vascular system. Through photic signal, circadian rhythm influences CNS, which then coordinates peripheral clocks of vascular cells. The alteration of eNOS, inflammatory cytokines and pro- and anti-thrombotic proteins promotes vascular damage and accelerates vascular aging. Furthermore, circadian rhythm dysregulation induces sleep disorders which increase vascular disease risk. CNS, central nervous system; eNOS, endothelial nitric oxide synthase.

FIGURE 2

The effects of microgravity on the vascular system. Microgravity decreases anti-oxidant defenses and induces mitochondrial dysfunction, thus increasing oxidative stress and impairing energy production and proteostasis. Dysregulation of lipid metabolism was found in astronauts which showed increased level of LDL and decreased level of HDL. Vascular cells exposed to microgravity showed morphological alterations, such as cytoskeletal dysregulation and shape and size variations. ROS, reactive oxygen species; LDL, low density lipoprotein; HDL, high density lipoprotein.

FIGURE 3

The effects of simulated microgravity on rodents’ cerebral arteries. Microgravity was simulated by HU (see text). Simulated microgravity induces initially vasoconstriction and then remodelling of rodents’ cerebral arteries. IP₃-R, inositol 1,4,5-trisphosphate receptor; FAK, focal adhesion kinase; α-SMA, alpha-smooth muscle actin; SM-MHC, smooth muscle-myosin heavy chain; OPN, osteopontin.

FIGURE 4

Countermeasures to protect vascular function during spaceflight and prevent post-flight orthostatic intolerance. Physical training and a correct and adequate nutrition improve intracellular redox balance and mitochondrial health, reduce the levels of systemic inflammatory markers and ameliorate endothelial function. Physical training also contributes to the arterial stiffness reduction, to prevent the bone and muscle loss and to resynchronize vascular clock.