Behringer Erik J, Leite Laura D, Buchholz Nickolaus E, Keeney Michael G, Pearce William J, Vanterpool Conwin K, Wilson Sean M, Buchholz John N
Department of Physiology and Pharmacology, Loma Linda Univ. School of Medicine, Loma Linda, CA 92350, USA.
J Appl Physiol (1985). 2009 Oct;107(4):1223-34. doi: 10.1152/japplphysiol.00363.2009. Epub 2009 Jul 30.
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 Ca(2+)-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 Ca(2+)-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.
来自颈上神经节（SCG）的交感神经对脑血管生长和功能的贡献在整个成熟过程中以及应对高原长期缺氧（LTH）所施加的心血管应激时都很重要。SCG交感神经元的功能依赖于细胞内钙离子浓度（[Ca2+]i）信号传导，这一过程受到一种称为从光滑内质网（SER）释放Ca2+诱导的Ca2+释放（CICR）的强烈影响。在本研究中，我们使用绵羊SCG神经元模型来检验以下假设：成熟会降低CICR，高原LTH会抑制胎儿SCG神经元而非成年SCG神经元的CICR。我们发现，CICR对电场刺激（EFS）诱发的[Ca2+]i瞬变的贡献在常氧胎儿的SCG细胞中最大，并且被LTH消除。CICR的下降与LTH期间胎儿SCG细胞中肌浆网Ca2+ - ATP酶（SERCA）功能的降低有关，使SER Ca2+水平降低到Ca2+内流与CICR偶联所需的阈值以下。关于从胎儿到成年的成熟过程，CICR的降低可能反映了兰尼碱受体亚型2和3水平以及SERCA功能的降低。与胎儿相反，在LTH刺激下，成年SCG细胞中的CICR功能得以维持，这可能反映了调节CICR过程的其他机制发生了改变。由于CICR在脑血管系统内交感神经元的功能中起重要作用，胎儿中这种信号机制的丧失可能会影响胎儿对血管损伤的易感性，从而影响其对LTH的适应。
