Glass Michael J, Chan June, Frys Kelly A, Oselkin Martin, Tarsitano M Jacqueline, Iadecola Costantino, Pickel Virginia M
Department of Neurology and Neuroscience, Weill Medical College of Cornell University, 411 E. 69th St., KB410, New York, NY 10021, USA.
Exp Neurol. 2007 Jun;205(2):383-95. doi: 10.1016/j.expneurol.2007.02.016. Epub 2007 Mar 3.
NADPH oxidase-generated superoxide can modulate crucial intracellular signaling cascades in neurons of the nucleus tractus solitarius (NTS), a brain region that plays an important role in cardiovascular processes. Modulation of NTS signaling by superoxide may be linked to the subcellular location of the mobile NADPH oxidase p47(phox) subunit, which is known to be present in dendrites of NTS neurons. It is not known, however, if hypertension can produce changes in the trafficking of p47(phox) in defined NTS subregions, particularly the preferentially barosensitive dorsomedial NTS (dmNTS), or preferentially gastrointestinal medial NTS (mNTS). We used immunogold electron microscopy to determine if p47(phox) localization was differentially affected in dendritic profiles of neurons from these NTS subregions of the rat in response to distinct models of hypertension, namely chronic 7-day subcutaneous administration of angiotensin II (AngII), or phenylephrine. In small (<1 microm) dendritic processes, both AngII and phenylephrine produced a decrease in intracellular p47(phox) labeling selectively in dmNTS neurons. In intermediate-size (1-2 microm) dendritic profiles in the dmNTS region only, there was an increase in p47(phox) labeling in response to each hypertensive agent, although these changes occurred in different subcellular compartments. There was an increase in non-vesicular labeling in response to AngII, but an increase in surface labeling with phenylephrine. Moreover, each of the changes in p47(phox) targeting mentioned above occurred in dendritic profiles with, or without immunoperoxidase labeling for the AngII AT-1A receptor subtype (AT-1A). These results indicate that chronic administration of agents that induce hypertension can also produce changes in the subcellular localization in p47(phox) in dmNTS neurons. Thus, systemic hypertension may produce alterations in the trafficking of proteins associated with superoxide production in central autonomic neurons, thus revealing a potentially important neurogenic component of free radical production and systemic blood pressure elevation.
烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶产生的超氧化物可调节孤束核（NTS）神经元中关键的细胞内信号级联反应，NTS是一个在心血管过程中起重要作用的脑区。超氧化物对NTS信号的调节可能与可移动的NADPH氧化酶p47（phox）亚基的亚细胞定位有关，已知该亚基存在于NTS神经元的树突中。然而，尚不清楚高血压是否会导致p47（phox）在特定的NTS亚区域，特别是对压力敏感的背内侧NTS（dmNTS）或优先对胃肠道敏感的内侧NTS（mNTS）中的运输发生变化。我们使用免疫金电子显微镜来确定在大鼠的这些NTS亚区域的神经元树突形态中，p47（phox）的定位是否因不同的高血压模型，即慢性7天皮下注射血管紧张素II（AngII）或去氧肾上腺素而受到不同影响。在小（<1微米）的树突状突起中，AngII和去氧肾上腺素均使dmNTS神经元中的细胞内p47（phox）标记选择性降低。仅在dmNTS区域的中等大小（1 - 2微米）的树突形态中，每种高血压药物都会使p47（phox）标记增加，尽管这些变化发生在不同的亚细胞区室中。AngII导致非囊泡标记增加，而去氧肾上腺素导致表面标记增加。此外，上述p47（phox）靶向的每种变化都发生在有或没有血管紧张素II AT - 1A受体亚型（AT - 1A）免疫过氧化物酶标记的树突形态中。这些结果表明，长期给予诱导高血压的药物也会使dmNTS神经元中p47（phox）的亚细胞定位发生变化。因此，全身性高血压可能会导致中枢自主神经元中与超氧化物产生相关的蛋白质运输发生改变，从而揭示自由基产生和全身性血压升高的一个潜在重要的神经源性成分。
