Among all environmental parameters that can alter cerebrovascular reactivity, variations in the level of gravity have been described as a candidate by re-equilibrating blood perfusion. Indeed, in human, reduced gravity such as that experienced in space, induces corporal fluids' re-distribution leading to the loss of head-to-foot hydrostatic pressure gradient (Convertino et al., 1989
; Norsk, 1992
; De Santo et al., 2001
). However, this is less evident in animal models such as rodents because of their quadruped station which obviously reduces the initial head-to-foot pressure gradient. The resulting effect of weightlessness achieved in spaceflights is a highly complex vascular adaptation to the increase in cardiac output by reducing the systemic vascular resistance, which limits the increase of blood pressure (reviewed in Norsk and Christensen, 2009
). It is suggested that the opposite effect is observed in cerebral arteries. The gravity changes can therefore induce a vascular adaptation to counteract any modification of cerebral perfusion.
Vascular dysfunctions are also described as risk factor or associated symptoms in several neurodegenerative diseases. Classically, ischemic stroke, atherosclerosis, hypertension, and cardiac disease have been reported to result in cerebrovascular disease and potentially trigger Alzheimer disease in older adults (de la Torre, 2009
; Viswanathan et al., 2009
; Austin et al., 2011
; Mazza et al., 2011
). Orthostatic hypotension, the result of the autonomic perturbation observed in astronauts after spaceflight, is also described as a complication or symptom in 18–81% of the Parkinsonian patients (Ha et al., 2011
). Another concomitant non-motor complication of Parkinson disease is the cognitive impairment and both are not stemmed with drug treatments reviewed by Lyons and Pahwa (2011
) and Jain and Goldstein (2012
). Thus, at this stage of our proposal, it is possible to link, on the one hand, cognitive impairments with modification of brain perfusion due to vascular dysfunction, and on the other hand the gravity changes and modifications of vascular function. Indeed, gravity changes could alter cognitive function via modulation of vascular reactivity.
In the brain, neuronal metabolism almost essentially implies glucose oxidation. Then, in all animal species, brain well-functioning closely depends on oxygen availability. Oxygen is brought to neurons by cerebral blood flow, which is at least in part, regulated by vascular smooth muscle cells (VSMCs) contractility/reactivity and depends on intracellular calcium concentrations. These last are regulated by the activity of three major classes of actors in the cells: (1) calcium entry through voltage- or non-voltage-dependent calcium channels at the plasma membrane, which initiates (2) calcium-dependent calcium release from endo-sarcoplasmic reticulum through inositol-1,4,5-trisphosphate receptors (InsP3R) and/or ryanodine receptors (RyRs), stopped thanks to (3) calcium stores refilling (Sarco/Endoplasmic Reticulum ATPase pumps, SERCA) or calcium extrusion (Plasma Membrane Calcium ATPase, PMCA). However, these phenomena are under the control of another calcium-signaling actor family composed of channels and regulators implicated in calcium entry and control of calcium stores refilling (STIM/ORAI/CRACR2 and SARAF).
Calcium signals regulate VSMCs reactivity. Briefly, vasoconstriction is due to propagated calcium waves encoded by InsP3R activation via G-Protein Coupled Receptor (GPCR)/PLCβ pathways or by RyR opening via calcium entry after depolarization (CaV channels) or cyclic-ADP ribose pathways activation reviewed in Morel et al. (2007
) and Berridge (2008
). But calcium signals also regulate vasorelaxation through localized and brief calcium signals named calcium sparks encoded by RyR and leading to the increase of activity of calcium-activated potassium channels named BKCa (Nelson et al., 1995
). Thus, as all excitable cells, the VSMCs also express many other ionic channels as potassium channels (Kitazono et al., 1995
) that are able to modulate membrane potential to regulate their level of contractility.
In fact, VSMCs reactivity can be modulated by neurons, either directly or via astrocytes, to adapt cerebral blood flow to cell needs, as well as by the endothelium to adapt vessels function to the blood pressure and cardiac output. As reviewed by Attwell et al. (2010
) the neuronal and glial control of brain blood flow is essential for oxygen and glucose inputs.
In Figure , we tried to summarize these neuroglial pathways: (1) in neurons, the presynaptic release of glutamate activates the post-synaptic NMDA receptor to encode calcium signal inducing activation of the neuronal nitric oxide (NO) synthase (nNOS) and vasodilatation (Domoki et al., 2002
; Zonta et al., 2003
; Busija et al., 2007
). The released NO can then modulate activity of RyR and calcium-activated potassium channels (BKCa) to hyperpolarize VSMCs and dilate cerebral artery (Mandala et al., 2007
; Yuill et al., 2010
); (2) glutamate also binds metabotropic receptors on the astrocyte membrane to activate a calcium wave (Filosa et al., 2004
) and cytochrome C oxydase (COX) to produce prostaglandin PGE2 and epoxyeicosatrienoic acid EET (Zonta et al., 2003
) responsible for vasodilatation via the increase of potassium channels activity (Filosa et al., 2006
). As summarized in Dunn and Nelson (2010
), the EET are produced by the action of cytochrome P450 epoxygenase CYP4A on 20-hydroxy-eicosatetraenoic acid (20-HETE). This enzymatic reaction increases vasodilatation by the produced EET known to increase BKCa activity directly or via the increase of calcium spark frequency; and also decreases the 20-HETE concentration (20-HETE is described to potentiate vasoconstriction via the inhibition of BKCa). The stimulation of potassium channels induces hyperpolarization and decreases the CaV activity. Other potassium channels expressed in VSMC are also implicated: inward rectifier potassium channels (KIR
) are activated by the increase of extracellular potassium concentration due to astrocyte's BKCa activation, and ATP-activated potassium channel (KATP
) activity is increased by phosphorylation by cAMP-dependent kinase PKA. Resulting vasodilation is necessary for the increase of dioxygen (O2
) and glucose availability for neurons, a cause of functional hyperemia. The opposite reaction is in part due to the VSMC contraction to decrease the exchange between blood and neurons. Vasoconstriction can be produced not only via GPCR activation by hormones like angiotensin-II evoking calcium waves (reviewed in Morel et al., 2007
), but also by 20-HETE derived from arachidonic acid (AA) that inhibits BKCa to depolarize the VSMC plasma membrane and consequently increases the calcium entry by CaV. The most studied pathways (PGE2, EET, and NO production) are sensitive to O2
concentrations at different levels, and then O2
can regulate vasodilatation and functional hyperemia by itself. But it is not excluded that other mechanisms may be activated to maintain or disrupt vasodilation and/or glucose and O2
transports. Thus, calcium signaling is a crucial step in the message transduction between cells in the neurogliovascular unit and for the regulation of VSMC contractile status. For these reasons, exploration of the calcium signals, in VSMC from animal models submitted to gravity changes, have been performed.
Figure 1 Neurogliovascular control of cerebral perfusion. Schematic representation of neuronal, astrocyte, and endothelial molecular control of vascular smooth muscle cells reactivity in the brain. AA, Arachidonic acid; AC, Adenylyl Cyclase; BKCa, Calcium-activated (more ...)
In this context, we recently demonstrated that spaceflight regulates portal vein myocytes calcium signaling in the opposite way of hypertension. More precisely, mice exposed to microgravity during an eight-day shuttle flight, as well as hindlimb unloaded rats, displayed decreased expression of RyR 1 expression in VSMCs from hepatic portal vein, associated with decreased calcium-induced calcium release signals. We demonstrated that these cells are per se
directly sensitive to microgravity and adapt their intracellular signaling even in culture preparations. In this study, we have shown for the first time that real and simulated microgravity applied on animals and cultured cells have similar effect in terms of gene expression. Interestingly, in spontaneously hypertensive rat's portal vein VSMCs, RyR 1 expression, and associated calcium signals were increased (Dabertrand et al., 2012
). Taken together, these recent data suggest that microgravity can effectively be modeled in rodents by caudal suspension, and acts in the same way as in human by decreasing peripheral blood vessels pressure when increasing cerebral arterial one.
When considering the hypergravity side of the problem, we are unfortunately forced to note that the effects of higher gravity levels on blood pressure are not well known. However, one can reasonably suppose that hypergravity can modify cerebral blood flow too. Our work in this field of investigation brought several lines of evidence supporting this hypothesis. For instance, and to respond to our previous works on microgravity, we recently investigated cerebral arteries VSMCs calcium signaling in adult male mice bred under hypergravity conditions (3G) during 21 days. If the breeding of animals in hypergravity is easier than raising a space module, the fact remains that the investigative methods must adapt to the small size of the samples and the large number of target to study. For example, RT-qPCR experiments, associated with western-blots and immunolabeling in mice may allow understanding how the expression of different pumps and channels may be affected by hypergravity. Then, it is noteworthy that gravity, as a physical constraint for the organism, can at least modulate cerebral, and thus cognitive, functions. However, studies in humans and rodents have only recently targeted learning and memory alterations in the field of altered gravity physiological effects, during development as well as at the adult stage (Sajdel-Sulkowska, 2008
; Zago et al., 2009