Spaceflight reduces vasoconstrictor responsiveness of skeletal muscle resistance arteries in mice

Abstract

Cardiovascular adaptations to microgravity undermine the physiological capacity to respond to orthostatic challenges upon return to terrestrial gravity. The purpose of the present study was to investigate the influence of spaceflight on vasoconstrictor and myogenic contractile properties of mouse gastrocnemius muscle resistance arteries. We hypothesized that vasoconstrictor responses acting through adrenergic receptors [norepinephrine (NE)], voltage-gated Ca(2+) channels (KCl), and stretch-activated (myogenic) mechanisms would be diminished following spaceflight. Feed arteries were isolated from gastrocnemius muscles, cannulated on glass micropipettes, and physiologically pressurized for in vitro experimentation. Vasoconstrictor responses to intraluminal pressure changes (0-140 cmH(2)O), KCl (10-100 mM), and NE (10(-9)-10(-4) M) were measured in spaceflown (SF; n = 11) and ground control (GC; n = 11) female C57BL/6 mice. Spaceflight reduced vasoconstrictor responses to KCl and NE; myogenic vasoconstriction was unaffected. The diminished vasoconstrictor responses were associated with lower ryanodine receptor-2 (RyR-2) and ryanodine receptor-3 (RyR-3) mRNA expression, with no difference in sarcoplasmic/endoplasmic Ca(2+) ATPase 2 mRNA expression. Vessel wall thickness and maximal intraluminal diameter were unaffected by spaceflight. The data indicate a deficit in intracellular calcium release via RyR-2 and RyR-3 in smooth muscle cells as the mechanism of reduced contractile activity in skeletal muscle after spaceflight. Furthermore, the results suggest that impaired end-organ vasoconstrictor responsiveness of skeletal muscle resistance arteries contributes to lower peripheral vascular resistance and less tolerance of orthostatic stress in humans after spaceflight.

V˙O2max and Microgravity Exposure

“…Conversely, the vasoconstrictor responses of arterioles from the soleus, which is primarily oxidative in nature, were not different from controls (21). Recent findings from Stabley et al (82) suggest a reduced vasoconstrictor response after spaceflight due to reduced intracellular calcium release from smooth muscle ryanodine receptors. In humans, forearm vasoconstrictor response to a cold pressor test during a reactive hyperemia blood flow maneuver was decreased after 14 d of bed rest (81), suggesting a potential mechanism for the altered distribution of Q during exercise.…”

“…After 2 wk of HU, arterioles from rat skeletal muscles composed primarily of type IIb fibers have a decreased response and sensitivity to the vasoconstrictor agonist KCl (82). Conversely, the vasoconstrictor responses of arterioles from the soleus, which is primarily oxidative in nature, were not different from controls (21).…”

“…To date, scientific investigations evaluating the vascular adaptations to microgravity have used both animal and human models. Delp and colleagues (4,21,22,(55)(56)(57)82) have extensively studied the microvascular responses to microgravity in the rat. Using a hind limb unloading (HU) protocol, investigators demonstrated that within the initial minutes of microgravity, muscle blood flow was decreased compared to baseline standing and remained depressed for up to 15 d (56), which are consistent with human spaceflight experiments (93).…”

“…The altered distribution of Q after microgravity is likely due to altered arterial vasodilation and vasoconstriction (4,21,22,55,81,82). After 2 wk of HU, arterioles from rat skeletal muscles composed primarily of type IIb fibers have a decreased response and sensitivity to the vasoconstrictor agonist KCl (82).…”

“…Likewise, significant cardiac atrophy is observed after microgravity exposure (26,63). However, relative to cardiac function, there are fewer investigations on the peripheral circulation, but evidence suggests that both structural and functional vascular adaptations occur (55,81,82). The pulmonary system is also altered by the removal of gravity (95), but postmicrogravity measurements of arterial saturation (SaO 2 ) and arterial partial pressure of oxygen (PaO 2 ) suggest that changes in pulmonary gas exchange are minimal (12,70).…”