Pituitary adenylate cyclase activating polypeptide: An important vascular regulator in human skin in vivo

Stephan Seeliger, Jörg Buddenkotte, Anjona Schmidt-Choudhury, Carine Rosignoli, Victoria Shpacovitch, Ulrike Von Arnim, Dieter Metze, Roman Rukwied, Martin Schmelz, Ralf Paus, Johannes J. Voegel, Wolfgang E. Schmidt, Martin Steinhoff

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

Pituitary adenylate cyclase-activating peptide (PACAP) is an important neuropeptide and immunomodulator in various tissues. Although this peptide and its receptors (ie , VPAC1R, VPAC2R, and PAC1R) are expressed in human skin, their biological roles are unknown. Therefore, we tested whether PACAP regulates vascular responses in human skin in vivo. When injected intravenously, PACAP induced a significant, concentration-dependent vascular response (ie, flush, erythema, edema) and mediated a significant and concentration-dependent increase in intrarectal body temperature that peaked at 2.7°C. Topical application of PACAP induced marked concentration-dependent edema. Immunohistochemistry revealed a close association of PACAP-immunoreactive nerve fibers with mast cells and dermal blood vessels. VPAC1R was expressed by dermal endothelial cells, CD4+ and CD8+ T cells, mast cells, and keratinocytes, whereas VPAC2R was expressed only in keratinocytes. VPAC1R protein and mRNA were also detected in human dermal microvascular endothelial cells. The PACAP-induced change in cAMP production in these cells demonstrated VPAC1R to be functional. PACAP treatment of organ-cultured human skin strongly increased the number of CD31+ vessel cross-sections. Taken together, these results suggest that PACAP directly induces vascular responses that may be associated with neurogenic inflammation, indicating for the first time that PACAP may be a crucial vascular regulator in human skin in vivo. Antagonists to PACAP function may be beneficial for the treatment of inflammatory skin diseases with a neurogenic component.

Original languageEnglish (US)
Pages (from-to)2563-2575
Number of pages13
JournalAmerican Journal of Pathology
Volume177
Issue number5
DOIs
StatePublished - Nov 2010
Externally publishedYes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Seeliger, S., Buddenkotte, J., Schmidt-Choudhury, A., Rosignoli, C., Shpacovitch, V., Von Arnim, U., Metze, D., Rukwied, R., Schmelz, M., Paus, R., Voegel, J. J., Schmidt, W. E., & Steinhoff, M. (2010). Pituitary adenylate cyclase activating polypeptide: An important vascular regulator in human skin in vivo. American Journal of Pathology, 177(5), 2563-2575. https://doi.org/10.2353/ajpath.2010.090941