**6. The heart of the matter: Circulation of blood in a gravitational environment**

obtained on Earth by *head down tilt*, *prolonged bed rest* or *dry water immersion* (Magrini et al., 1992), in flight, during the fall phase of *parabolic flight in jet aircraft* or in orbit around the Earth

Since these techniques counteract some of the effects of gravity, it is believed they can provide

Unfortunately the precise role of gravity on evolution is difficult to determine in complex organisms because, until now, the stay in a *microgravity environment* has been too limited and no higher vertebrate has passed at least one life cycle in microgravity to see the effects on subsequent generations. These simulations, even if limited in time, may nevertheless provide useful information on *adaptive processes* to counteract the force of gravity in different organisms and, in such sense, the responses of the cardiovascular system are paradigmatic. Previous observations suggests that prolonged dry water immersion after birth in rats is able to dissociate the effects of body growth and aging on systolic blood pressure since the micro‐ gravity reduces the needing for load-bearing structures and then the body weight, temporarily

It should be remarked that the ability to survive in a gravitational environment is inversely proportional to the size, in other words unicellular organisms such as bacteria are much less sensitive to gravity when compared to complex organisms with blood circulation and subject to cyclical postural changes. These observations are derived from the study of extremophiles, i.e organisms capable of surviving in extreme environments and similar to those that are supposed to exist on other planets (Rothschild and Mancinelli, 2001; Brack and Pillinger, 1998). Due to this lower sensitivity to changes in gravity, as demonstrated also by the growth at hyper-accelerations (Deguchi et al., 2011) and also to the high level of resistance in all ecosys‐ tems, bacteria have indeed the potential to travel in space and colonize planets with different gravity levels. This theoretical possibility, and some studies on meteorites, have led to the suggestive hypothesis that life on Earth has an extraterrestrial origin thanks to space vectors such as meteorites or asteroids (Mautner, 2002). This kind of exogenesis, challenged at the

important information relevant to biology in a gravitational environment.

with *spacecraft* (Table 3).

662 Regenerative Medicine and Tissue Engineering

**Table 3.** Experimental approaches to simulate microgravity

blunting systolic blood pressure rise (Magrini et al., 1992).

Despite little changes over time in the Earth's gravitational field, the effects of gravity on living organisms cannot be properly appreciated without taking into account some factors related to the development of multicellularity that have introduced significant changes in the experiment of life on earth. Among these factors, the development of blood circulation and the propensity to postural change have certainly contributed to substantially increase the role of gravitational factors.

In complex organisms the development of a cardiovascular system fulfills the need for transport of nourishment, oxygen and metabolic waste as well as the need for communication between distant districts (Ciulla et al., 2011). The impacts of the *assumption of standing posi‐ tion* in mammals during evolution may have represented a real challenge for the cardiovascular system and, certainly a step forward in the freedom to move in space (Gisolf, 2005). This challenge presents itself in every individual after birth when the assumption of the upright position translocates the intravascular volume from the cardiopulmonary area to the periphery eliciting appropriate *neuro-humoral responses* whose objective is to control the dynamics of body fluids and blood pressure in a gravitational environment (Magrini et al., 1989). It should be recalled at this point that the heart of higher vertebrates is a quite complex multi-chambered pump that contracts synchronously; for its function, a number of components have to be generated; thus not surprisingly, several factors are involved in regulating the target genes responsible for both morphogenesis and function (Hoogaars et al., 2007).

Indeed the cardiovascular system begins to adapt to the gravitational loading before birth and, in particular, when the fetus, growing, begins to come into contact with the amniotic sac (Sekulic et al., 2005). This takes place towards the end of the pregnancy and is essential for the proper development of *sensory receptors* (Bradley and Mistretta, 1975) thus the microgravity resulting from immersion in the amniotic fluid does not mask the effects of gravity on the fetus. After birth, the newborn is immediately exposed to the gravitational load that, as we have seen, also varies depending on the posture. Exposure to gravitational stimuli may also have played a key role in the evolution of the position of the heart in relation to the circulation; taking, for example, three types of snakes that live in different environments, such as trees, land and sea, it was noticed that the position of the heart is closer or more distant from the head as a function of the gravitational load, being more distant in water snakes (Lillywhite, 1988). Therefore, even if gravity is a rather constant parameter on earth, it conditions the development of living organisms, before and after birth, with an increasing impact depending on having a blood circulation and, at the same time, on the propensity to postural change, and both of these characteristics are typical of higher vertebrates.

Finally, several findings suggest that gravity continues to play a decisive role *during aging*, since the reduction of loading conditions that characterizes the more sedentary life typical of the elderly has important effects on the organism that resemble, in many respects, to what happens in microgravity environment during prolonged space flight (Vernikos and Schneider, 2010). In particular, the reduction of motion and acceleration typical of *aging* and of the *prolonged space flight*, can decondition the cardiovascular reflexes, altering the control of blood pressure with *orthostatic hypotension*, and lead to a reduction of muscle mass and the loss of calcium from the bones.
