Sex differences in the control of acral skin blood flow in humans: differential regulation of cyclooxygenase in ýý-adrenergic signalling.
Sex differences in the control of acral skin blood flow in humans: differential regulation of cyclooxygenase in ýý-adrenergic signalling.
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人类肢端皮肤血流控制的性别差异：α-肾上腺素信号传导中环氧合酶的差异调节。
DOI：
10.1113/jphysiol.2011.218859
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发表时间：
2011
期刊：
影响因子：
--
通讯作者：
Holowatz,LacyA
中科院分区：
文献类型：
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作者：
Holowatz,LacyA
人体皮肤血液流动的综合神经血管控制是复杂的，功能服务于人体独特的体温调节需求。大约95%的人体皮肤是非肢端（多毛），受交感神经系统胆碱能和肾上腺素能分支的调节（Roddie, 1957; Kellogg et al. 1995）。另外5%的人类皮肤是肢端皮肤（无毛），主要位于手、脚和面部部分，由交感肾上腺素能机制控制（Roddie et al. 1957）。然而，精确的神经血管机制，特别是关于肾上腺素受体（AR）信号，介导人体肢端皮肤血流量的控制尚不清楚。肢端皮肤血管致密，有两种不同的受体亚型，包括α1和α2- ar。α2- ar有三种不同的亚型（α2A、α2B和αC2），它们在人指动脉中表现突出，在信号放大中起着重要的机制作用，从而启动强大的血管收缩。这些机制在包括原发性雷诺氏病在内的许多病理状态中失调。该病在女性中的发病率高于男性，提示女性生殖激素对α-AR信号的潜在影响（Cooke & Marshall, 2005）。因此，了解性激素对α-AR信号传导的影响具有重要的临床意义。在最近一期的《生理学杂志》上，Marshall & Srinivasa（2011）报告了他们在一系列研究中的发现，他们研究了性和月经周期对α1和α2受体激动剂离子吸氧作用下手指血流控制的影响。他们进一步研究了环加氧酶信号在这些机制中的作用。具体来说，这些作者假设，在高雌激素暴露的条件下，由于cox依赖性血管收缩剂（包括前列腺素H2和血栓素A2）的增加，α - 1激动剂苯肾上腺素的血管收缩会更大。他们进一步假设，特异性α2激动剂可乐定诱导的血管收缩可能由于COX合成血管扩张剂的增加和内皮源性NO的增加而减弱。作者的假设是从健全的动物实验和先前对人类的观察中发展而来的。这些作者应该受到赞扬，他们采用创新的方法在体内人体模型中检查临床相关的复杂神经血管信号机制。这项研究中出现了许多新的发现，表明男性和女性血管收缩的差异是由cox依赖性血管收缩剂和血管舒张剂的产生介导的。特别是在男性中，苯肾上腺素引起最初的血管扩张，这依赖于cox衍生的血管扩张剂的合成，然后逐渐收缩。在月经周期卵泡期早期的女性中，苯肾上腺素的血管收缩反应不受COX机制的影响。相反，在黄体期，血管收缩仅在全身COX抑制后观察到。这些数据表明雌激素调节cox衍生血管活性分子的合成和/或终器官反应性。这项研究强调了在体内人体模型中检查血管信号机制的复杂性。首先，当使用药物激动剂和拮抗剂时，必须考虑腔内和腔外的潜在作用。为了具体检验
The integrative neurovascular control of human skin blood flow is complex and functions to serve the unique thermoregulatory needs of the human body. Approximately, 95% of human skin is non-acral (hairy) and is regulated by both cholinergic and adrenergic branches of the sympathetic nervous system (Roddie, 1957; Kellogg et al. 1995). The other 5% of human skin is acral skin (non-hairy) located primarily on the hands, feet, and parts of the face and is controlled via sympathetic adrenergic mechanisms (Roddie et al. 1957). However, the precise neurovascular mechanisms, especially with respect to adrenoreceptor (AR) signalling, mediating the control of acral skin blood flow in humans is unclear. Acral skin vessels are dense with two distinct receptor subtypes including α1-and α2-ARs. The α2-ARs have three distinct subtypes (α2A, α2B and αC2) which are prominent in human digital arteries and mechanistically important for signal amplification to initiate a robust vasoconstriction. These mechanisms are dysregulated in a number of pathological states including primary Raynauds disease. The incidence of this disease is more common in women than men, suggesting the potential influences of female reproductive hormones on α-AR signalling (Cooke & Marshall, 2005). Therefore, understanding the influence of sex hormones on α-AR signalling has significant clinical relevance. In a recent issue of The Journal of Physiology, Marshall & Srinivasa (2011) report their findings in a series of studies where they examined sex and menstrual cycle effects on the control of finger blood flow in response to iontophoretic administration of α1-and α2-receptor agonist. They further investigate the contribution of cyclooxygenase signalling to these mechanisms. Specifically, these authors postulated that under conditions of high oestrogen exposure there would be a greater vasoconstriction to the α1-agonist phenylephrine due to an increase in COX-dependent vasoconstrictors including prostaglandin H2 and thromboxane A2. They further postulated that the vasoconstriction induced by the specific α2-agonist clonidine would be attenuated due to an increase in COX synthesized vasodilators and possibly an increase in endothelial derived NO. The authors’ hypotheses were developed from sound animal experiments and previous observations in humans.These authors should be commended for employing innovative methodology to examine clinically relevant complex neurovascular signalling mechanisms in an in vivo human model. Many novel findings have emerged from this study, showing differential vasoconstriction in men and women mediated by the production of both COX-dependent vasoconstrictors and vasodilators. Specifically in men phenylephrine caused an initial vasodilatation that was dependent upon the synthesis of COX-derived vasodilators and then a graded constriction. In women during the early follicular phase of the menstrual cycle vasoconstriction in response to phenylephrine was not influenced by COX mechanisms. In contrast during the luteal phase vasoconstriction was only observed after systemic COX inhibition. These data suggest that oestrogen modulates the synthesis of COX-derived vasoactive molecules and/or the end-organ responsiveness. This study highlights the complexities of examining vascular signalling mechanisms in an in vivo human model. First, when pharmacological agonists and antagonists are used both the intraluminal and extraluminal potential effects must be considered. In order to specifically examine