Maturation and long-term hypoxia alters Ca²⁺-induced Ca²⁺release in sheep cerebrovascular sympathetic neurons

Abstract

The contribution of sympathetic nerves arising from the superior cervical ganglia (SCG) toward the growth and function of cerebral blood vessels is pertinent throughout maturation as well as in response to cardiovascular stress imposed by high-altitude long-term hypoxia (LTH). The function of SCG sympathetic neurons is dependent on intracellular Ca2+ concentration ([Ca2+]i) signaling, which is strongly influenced by a process known as Ca2+-induced Ca2+ release (CICR) from the smooth endoplasmic reticulum (SER). In this study, we used the sheep SCG neuronal model to test the hypotheses that maturation decreases CICR and high-altitude LTH depresses CICR in fetal SCG neurons but not in those of the adult. We found that the contribution of CICR to electric field stimulation (EFS)-evoked [Ca2+]i transients was greatest in SCG cells from normoxic fetuses and was abolished by LTH. The decline in CICR was associated with a reduction in sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) function in fetal SCG cells during LTH, reducing SER Ca2+ levels below the threshold needed for the coupling of Ca2+ influx and CICR. With respect to the maturation from the fetus to adult, the decrease in CICR may reflect both a reduction in the levels of ryanodine receptor isoforms 2 and 3 and SERCA function. In response to LTH and in contrast to the fetus, CICR function in adult SCG cells is maintained and may reflect alterations in other mechanisms that modulate the CICR process. As CICR is instrumental in the function of sympathetic neurons within the cerebrovasculature, the loss of this signaling mechanism in the fetus may have consequences for the adaptation to LTH in terms of fetal susceptibility to vascular insults.

Maternal high-altitude hypoxia and suppression of ryanodine receptor-mediated Ca2+ sparks in fetal sheep pulmonary arterial myocytes

“…Notably, we have shown that caffeine elicits Ca 2ϩ responses in nearly all PA myocytes from fetal sheep, and the events have greater amplitude compared with adults (8). This also occurs in superior cervical ganglion neurons from these fetal sheep (1). Together, these findings provide support that RyRs are functional in utero in sheep PA myocytes and that their function may change following birth.…”

Melatonin improves cerebrovascular function and decreases oxidative stress in chronically hypoxic lambs

“…Interestingly, there is evidence of successful high‐altitude long‐term hypoxia acclimatization, with increases in carotid blood blow and no compromise in cerebral oxygenation . However, this adaptation is correlated with a significant intra‐uterine growth restriction and altered vascular functions . Moreover, the responses to high‐altitude long‐term hypoxia may effectively program cerebrovascular diseases at adulthood as vascular development and function require a finely controlled environment .…”

The Fetal Cerebral Circulation: Three Decades of Exploration by the LLU Center for Perinatal Biology

“…In other studies, chronic hypoxia decreased cerebrovascular nNOS abundance, due presumably to decreased innervation by nitridergic nerves, particularly in immature arteries [116]. Ex vivo neurophysiological studies also demonstrated that chronic hypoxia can markedly attenuate calcium-induced calcium release, SERCA function, and subsequent norepinephrine release in fetal sympathetic neurons [117]. …”