Sodium channel Nav1.7 in vascular myocytes, endothelium, and innervating axons in human skin
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RESEARCH
MOLECULAR PAIN Open Access
Sodium channel Nav1.7 in vascular myocytes, endothelium, and innervating axons in human skin Frank L Rice1, Phillip J Albrecht1,2, James P Wymer2, Joel A Black3,4, Ingemar SJ Merkies5,6, Catharina G Faber6 and Stephen G Waxman3,4*
Abstract Background: The skin is a morphologically complex organ that serves multiple complementary functions, including an important role in thermoregulation, which is mediated by a rich vasculature that is innervated by sympathetic and sensory endings. Two autosomal dominant disorders characterized by episodes of severe pain, inherited erythromelalgia (IEM) and paroxysmal extreme pain disorder (PEPD) have been directly linked to mutations that enhance the function of sodium channel Nav1.7. Pain attacks are accompanied by reddening of the skin in both disorders. Nav1.7 is known to be expressed at relatively high levels within both dorsal root ganglion (DRG) and sympathetic ganglion neurons, and mutations that enhance the activity of Nav1.7 have been shown to have profound effects on the excitability of both cell-types, suggesting that dysfunction of sympathetic and/or sensory fibers, which release vasoactive peptides at skin vasculature, may contribute to skin reddening in IEM and PEPD. Results: In the present study, we demonstrate that smooth muscle cells of cutaneous arterioles and arteriole-venule shunts (AVS) in the skin express sodium channel Nav1.7. Moreover, Nav1.7 is expressed by endothelial cells lining the arterioles and AVS and by sensory and sympathetic fibers innervating these vascular elements. Conclusions: These observations suggest that the activity of mutant Nav1.7 channels in smooth muscle cells of skin vasculature and innervating sensory and sympathetic fibers contribute to the skin reddening and/or pain in IEM and PEPD. Keywords: Arteriole-venule shunt, Cutaneous arterioles, Dermis, Smooth muscle cells, Sodium channels, Vascular myocytes
Introduction The skin is a morphologically complex organ that serves multiple complementary functions [1]. While fulfilling a protective role, the skin is an exquisite tactile sense organ designed to detect a wide variety of mechanical, thermal, chemical, and noxious stimuli over a wide range of intensities. In humans, the skin, particularly of the hands and feet, also plays an important role in thermoregulation [2-5]. These varied functions are subserved through a mix of discrete structures including the epidermis, dermal papillae, and a rich vasculature that are innervated by a * Correspondence: [email protected] 3 Center for Neuroscience & Regeneration Research, Yale University School of Medicine, West Haven, CT 06516, USA 4 Rehabilitation Research Center, VA Connecticut Healthcare System, West Haven, CT 06516, USA Full list of author information is available at the end of the article
variety of sympathetic and sensory nerve endings. While providing a high degree of versatility, the complexity of the skin and its innervation contributes to susceptibility to sensory neuropathies and sud
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