Pituitary adenylate cyclase activating polypeptide: an important vascular regulator in human skin in vivo.
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.
Seeliger
Stephan
S
Department of Pediatrics III, University of Göttingen, Göttingen, Germany.
Buddenkotte
Jörg
J
Schmidt-Choudhury
Anjona
A
Rosignoli
Carine
C
Shpacovitch
Victoria
V
von Arnim
Ulrike
U
Metze
Dieter
D
Rukwied
Roman
R
Schmelz
Martin
M
Paus
Ralf
R
Voegel
Johannes J
JJ
Schmidt
Wolfgang E
WE
Steinhoff
Martin
M
D000328:Adult; D006801:Humans; D008297:Male; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000378:metabolism* / Q000494:pharmacology; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I / Q000235:genetics / Q000378:metabolism; D051239:Receptors, Vasoactive Intestinal Peptide, Type II / Q000235:genetics / Q000378:metabolism; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I / Q000235:genetics / Q000378:metabolism; D012039:Regional Blood Flow; D012867:Skin / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism*; D046509:Tissue Culture Techniques; D014581:Urticaria / Q000378:metabolism / Q000473:pathology; D014660:Vasoactive Intestinal Peptide / Q000378:metabolism / Q000494:pharmacology; D055815:Young Adult
D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; D051239:Receptors, Vasoactive Intestinal Peptide, Type II; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; D014660:Vasoactive Intestinal Peptide