Boerman Erika M, Segal Steven S
Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO, 65212, USA.
Dalton Cardiovascular Research Center, Columbia, MO, 65211, USA.
J Physiol. 2016 Apr 15;594(8):2323-38. doi: 10.1113/JP270710. Epub 2015 Jun 30.
The dilatory role for sensory innervation of mesenteric arteries (MAs) is impaired in Old (∼24 months) versus Young (∼4 months) mice. We investigated the nature of this impairment in isolated pressurized MAs. With perivascular sensory nerve stimulation, dilatation and inhibition of sympathetic vasoconstriction observed in Young MAs were lost in Old MAs along with impaired dilatation to calcitonin gene-related peptide (CGRP). Inhibiting NO and prostaglandin synthesis increased CGRP EC50 in Young and Old MAs. Endothelial denudation attenuated dilatation to CGRP in Old MAs yet enhanced dilatation to CGRP in Young MAs while abolishing all dilatations to ACh. In Old MAs, sensory nerve density was reduced and RAMP1 (CGRP receptor component) associated with nuclear regions of endothelial cells in a manner not seen in Young MAs or in smooth muscle cells of either age. With advanced age, loss of dilatory signalling mediated through perivascular sensory nerves may compromise perfusion of visceral organs.
Vascular dysfunction and sympathetic nerve activity increase with advancing age. In the gut, blood flow is governed by perivascular sensory and sympathetic nerves but little is known of how their functional role is affected by advanced age. We tested the hypothesis that functional sensory innervation of mesenteric arteries (MAs) is impaired for Old (24 months) versus Young (4 months) C57BL/6 male mice. In cannulated pressurized MAs preconstricted 50% with noradrenaline and treated with guanethidine (to inhibit sympathetic neurotransmission), perivascular nerve stimulation (PNS) evoked dilatation in Young but not Old MAs while dilatations to ACh were not different between age groups. In Young MAs, capsaicin (to inhibit sensory neurotransmission) blocked dilatation and increased constriction during PNS. With no difference in efficacy, the EC50 of CGRP as a vasodilator was ∼6-fold greater in Old versus Young MAs. Inhibiting nitric oxide (l-NAME) and prostaglandin (indomethacin) synthesis increased CGRP EC50 in both age groups. Endothelial denudation reduced the efficacy of dilatation to CGRP by ∼30% in Old MAs yet increased this efficacy ∼15% in Young MAs while all dilatations to ACh were abolished. Immunolabelling revealed reduced density of sensory (CGRP) but not sympathetic (tyrosine hydroxylase) innervation for Old versus Young MAs. Whereas the distribution of CGRP receptor proteins was similar in SMCs, RAMP1 associated with nuclear regions of endothelial cells of Old but not Young MAs. With advanced age, the loss of sensory nerve function and diminished effectiveness of CGRP as a vasodilator is multifaceted and may adversely affect splanchnic perfusion.
与年轻（约4个月）小鼠相比，老年（约24个月）小鼠肠系膜动脉（MA）的感觉神经支配的舒张作用受损。我们在离体加压MA中研究了这种损伤的性质。随着血管周围感觉神经刺激，年轻MA中观察到的舒张以及对交感神经血管收缩的抑制在老年MA中消失，同时对降钙素基因相关肽（CGRP）的舒张作用受损。抑制一氧化氮（NO）和前列腺素合成会增加年轻和老年MA中CGRP的半数有效浓度（EC50）。内皮剥脱减弱了老年MA中对CGRP的舒张作用，但增强了年轻MA中对CGRP的舒张作用，同时消除了对乙酰胆碱（ACh）的所有舒张反应。在老年MA中，感觉神经密度降低，并且受体活性修饰蛋白1（RAMP1，CGRP受体成分）与内皮细胞核区域相关联，这种方式在年轻MA或任何年龄的平滑肌细胞中均未见到。随着年龄增长，通过血管周围感觉神经介导的舒张信号传导丧失可能会损害内脏器官的灌注。
血管功能障碍和交感神经活动随年龄增长而增加。在肠道中，血流由血管周围感觉神经和交感神经控制，但对于它们的功能作用如何受衰老影响知之甚少。我们测试了一个假设，即对于老年（24个月）与年轻（4个月）的C57BL / 6雄性小鼠，肠系膜动脉（MA）的功能性感觉神经支配受损。在用去甲肾上腺素预收缩50%并用地巴唑（以抑制交感神经传递）处理的插管加压MA中，血管周围神经刺激（PNS）在年轻MA中引起舒张，但在老年MA中未引起舒张，而不同年龄组之间对ACh的舒张反应无差异。在年轻MA中，辣椒素（以抑制感觉神经传递）在PNS期间阻断舒张并增加收缩。在疗效无差异的情况下，CGRP作为血管舒张剂的EC50在老年MA中比年轻MA大约高6倍。抑制一氧化氮（L - NAME）和前列腺素（吲哚美辛）合成会增加两个年龄组中CGRP的EC50。内皮剥脱使老年MA中对CGRP的舒张效力降低约30%，但使年轻MA中该效力增加约15%，同时消除了对ACh的所有舒张反应。免疫标记显示，与年轻MA相比，老年MA中感觉（CGRP）神经而非交感（酪氨酸羟化酶）神经支配的密度降低。虽然CGRP受体蛋白在平滑肌细胞中的分布相似，但RAMP1与老年MA而非年轻MA的内皮细胞核区域相关联。随着年龄增长，感觉神经功能丧失以及CGRP作为血管舒张剂的效力降低是多方面的，可能会对内脏灌注产生不利影响。
