Journal of Molecular Neuroscience

, Volume 48, Issue 3, pp 574–583 | Cite as

Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Potently Dilates Middle Meningeal Arteries: Implications for Migraine

  • Arsalan U. Syed
  • Masayo Koide
  • Karen M. Braas
  • Victor May
  • George C. WellmanEmail author


Migraine is a debilitating neurological disorder characterized by mild to severe headache that is often accompanied by aura and other neurological symptoms. Among proposed mechanisms, dilation of the dural vasculature especially the middle meningeal artery (MMA) has been implicated as one component underlying this disorder. Several regulatory peptides from trigeminal sensory and sphenopalatine postganglionic parasympathetic fibers innervating these vessels have been implicated in the process including pituitary adenylate cyclase-activating polypeptide (PACAP). Although PACAP has been well described as a potent dilator in many vascular beds, the effects of PACAP on the dural vasculature are unclear. In the current study, we examined the ability of PACAP to dilate MMAs that were isolated from rats and pressurized ex vivo. PACAP38 potently dilated pressurized MMAs with an EC50 of 1 pM. The PAC1 receptor antagonist, PACAP(6-38), abolished MMA dilation caused by picomolar concentrations of PACAP. In contrast, cerebellar arteries isolated from the brain surface were ~1,000-fold less sensitive to PACAP than MMAs. Although cerebellar arteries expressed transcripts for all three PACAP receptor subtypes (PAC1, VPAC1, and VPAC2 receptors) by RT-PCR analyses, MMA demonstrated only PAC1 and VPAC2 receptor expression. Further, multiple variants of the PAC1 receptor were identified in the MMA. The expression of PAC1 receptors and the high potency of PACAP to induce MMA vasodilation are consistent with their potential roles in the etiology of migraine.


Migraine Vascular smooth muscle Neurotransmitter Pituitary adenylate cyclase-activating polypeptide (PACAP) Calcitonin gene-related peptide (CGRP) 



The authors wish to thank Mr. Kevin O'Connor for his assistance and acknowledge the University of Vermont Neuroscience COBRE molecular biology core facility. This work was supported by the Totman Medical Research Trust and National Institutes of Health Grants P01-HL-2095488, P20-RR-16435, and R01-HL-078983.


No conflicts of interest, financial or otherwise, are declared by the authors.


  1. Amin FM, Asghar MS, Guo S et al (2012) Headache and prolonged dilatation of the middle meningeal artery by PACAP38 in healthy volunteers. Cephalalgia 32:140–149PubMedCrossRefGoogle Scholar
  2. Asghar MS, Hansen AE, Amin FM et al (2011) Evidence for a vascular factor in migraine. Ann Neurol 69:635–645PubMedCrossRefGoogle Scholar
  3. Baun M, Hay-Schmidt A, Edvinsson L, Olesen J, Jansen-Olesen I (2011) Pharmacological characterization and expression of VIP and PACAP receptors in isolated cranial arteries of the rat. Eur J Pharmacol 670:186–194PubMedCrossRefGoogle Scholar
  4. Bayliss WM (1902) On the local reactions of the arterial wall to changes of internal pressure. J Physiol (Lond) 28:220–231Google Scholar
  5. Boni LJ, Ploug KB, Olesen J, Jansen-Olesen I, Gupta S (2009) The in vivo effect of VIP, PACAP-38 and PACAP-27 and mRNA expression of their receptors in rat middle meningeal artery. Cephalalgia 29:837–847PubMedCrossRefGoogle Scholar
  6. Braas KM, May V (1999) Pituitary adenylate cyclase-activating polypeptides directly stimulate sympathetic neuron neuropeptide Y release through PAC(1) receptor isoform activation of specific intracellular signaling pathways. J Biol Chem 274:27702–27710PubMedCrossRefGoogle Scholar
  7. Brain SD, Williams TJ, Tippins JR, Morris HR, MacIntyre I (1985) Calcitonin gene-related peptide is a potent vasodilator. Nature 313:54–56PubMedCrossRefGoogle Scholar
  8. Burstein R, Jakubowski M (2005) Implications of multimechanism therapy: when to treat? Neurology 64:16–20CrossRefGoogle Scholar
  9. Collins PY, Patel V, Joestl SS et al (2011) Grand challenges in global mental health. Nature 475:27–30PubMedCrossRefGoogle Scholar
  10. Csati A, Tajti J, Kuris A et al (2012) Distribution of vasoactive intestinal peptide, pituitary adenylate cyclase-activating peptide, nitric oxide synthase, and their receptors in human and rat sphenopalatine ganglion. Neuroscience 202:158–168PubMedCrossRefGoogle Scholar
  11. Dejda A, Seaborn T, Bourgault S et al (2011) PACAP and a novel stable analog protect rat brain from ischemia: insight into the mechanisms of action. Peptides 32:1207–1216PubMedCrossRefGoogle Scholar
  12. Dickinson T, Fleetwood-Walker SM, Mitchell R, Lutz EM (1997) Evidence for roles of vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase activating polypeptide (PACAP) receptors in modulating the responses of rat dorsal horn neurons to sensory inputs. Neuropeptides 31:175–185PubMedCrossRefGoogle Scholar
  13. Dunn WR, Wellman GC, Bevan JA (1994) Enhanced resistance artery sensitivity to agonists under isobaric compared with isometric conditions. Am J Physiol Heart Circ Physiol 266:H147–H155Google Scholar
  14. Fahrenkrug J, Hannibal J, Tams J, Georg B (2000) Immunohistochemical localization of the VIP1 receptor (VPAC1R) in rat cerebral blood vessels: relation to PACAP and VIP containing nerves. J Cereb Blood Flow Metab 20:1205–1214PubMedCrossRefGoogle Scholar
  15. Goadsby PJ, Edvinsson L (1993) The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Ann Neurol 33:48–56PubMedCrossRefGoogle Scholar
  16. Hansen JM, Sitarz J, Birk S et al (2006) Vasoactive intestinal polypeptide evokes only a minimal headache in healthy volunteers. Cephalalgia 26:992–1003PubMedCrossRefGoogle Scholar
  17. Harmar AJ, Fahrenkrug J, Gozes I et al (2012) Pharmacology and functions of receptors for vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide: IUPHAR Review 1. Br J Pharmacol 166:4–17PubMedCrossRefGoogle Scholar
  18. Ishiguro M, Puryear CB, Bisson E et al (2002) Enhanced myogenic tone in cerebral arteries from a rabbit model of subarachnoid hemorrhage. Am J Physiol Heart Circ Physiol 283:H2217–H2225PubMedGoogle Scholar
  19. Johnson PC (1980) The myogenic response, vascular smooth muscle II. In: Bohr DF, Somlyo AP, Sparks HV Jr (eds) Handbook of physiology; Section 2: The cardiovascular system. American Physiological Society, Bethesda, pp 409–44Google Scholar
  20. Lassen LH, Haderslev PA, Jacobsen VB et al (2002) CGRP may play a causative role in migraine. Cephalalgia 22:54–61PubMedCrossRefGoogle Scholar
  21. Mayberg M, Langer RS, Zervas NT, Moskowitz MA (1981) Perivascular meningeal projections from cat trigeminal ganglia: possible pathway for vascular headaches in man. Science 213:228–230PubMedCrossRefGoogle Scholar
  22. McCulloch J, Uddman R, Kingman TA, Edvinsson L (1986) Calcitonin gene-related peptide: functional role in cerebrovascular regulation. Proc Natl Acad Sci U S A 83:5731–5735PubMedCrossRefGoogle Scholar
  23. Michalicek J, Gordon V, Lambert G (1996) Autoregulation in the middle meningeal artery. J Cereb Blood Flow Metab 16:507–516PubMedCrossRefGoogle Scholar
  24. Miyata A, Arimura A, Dahl RR et al (1989) Isolation of a novel 38 residue-hypothalamic polypeptide which stimulates adenylate cyclase in pituitary cells. Biochem Biophys Res Commun 164:567–574PubMedCrossRefGoogle Scholar
  25. Nelson MT, Cheng H, Rubart M et al (1995) Relaxation of arterial smooth muscle by calcium sparks. Science 270:633–637PubMedCrossRefGoogle Scholar
  26. Nystoriak MA, Murakami K, Penar PL, Wellman GC (2009) CaV1.2 splice variant with exon 9* is critical for regulation of cerebral artery diameter. Am J Physiol Heart Circ Physiol 297:H1820–H1828PubMedCrossRefGoogle Scholar
  27. Nystoriak MA, O'Connor KP, Sonkusare SK et al (2011) Fundamental increase in pressure-dependent constriction of brain parenchymal arterioles from subarachnoid hemorrhage model rats due to membrane depolarization. Am J Physiol Heart Circ Physiol 300:H803–H812PubMedCrossRefGoogle Scholar
  28. Olesen J, Burstein R, Ashina M, Tfelt-Hansen P (2009) Origin of pain in migraine: evidence for peripheral sensitisation. Lancet Neurol 8:679–690PubMedCrossRefGoogle Scholar
  29. Rahmann A, Wienecke T, Hansen JM et al (2008) Vasoactive intestinal peptide causes marked cephalic vasodilation, but does not induce migraine. Cephalalgia 28:226–236PubMedCrossRefGoogle Scholar
  30. Ray BS, Wolff HG (1940) Experimental studies on headache: pain-sensitive structures of the head and their significance in headache. Arch Surg 41:813–856CrossRefGoogle Scholar
  31. Schytz HW, Birk S, Wienecke T et al (2009) PACAP38 induces migraine-like attacks in patients with migraine without aura. Brain 132:1–25Google Scholar
  32. Schytz HW, Olesen J, Ashina M (2010) The PACAP receptor: a novel target for migraine treatment. Neurotherapeutics 7:191–196PubMedCrossRefGoogle Scholar
  33. Seki Y, Suzuki Y, Baskaya MK et al (1995) The effects of pituitary adenylate cyclase-activating polypeptide on cerebral arteries and vertebral artery blood flow in anesthetized dogs. Eur J Pharmacol 275:259–266PubMedCrossRefGoogle Scholar
  34. Simons T, Ruskell GL (1988) Distribution and termination of trigeminal nerves to the cerebral arteries in monkeys. J Anat 159:57–71PubMedGoogle Scholar
  35. Spengler D, Waeber C, Pantaloni C et al (1993) Differential signal transduction by five splice variants of the PACAP receptor. Nature 365:170–175PubMedCrossRefGoogle Scholar
  36. Vaudry D, Falluel-Morel A, Bourgault S et al (2009) Pituitary adenylate cyclase-activating polypeptide and its receptors: 20 years after the discovery. Pharmacol Rev 61:283–357PubMedCrossRefGoogle Scholar
  37. Yamada H, Watanabe M, Yada T (2004) Cytosolic Ca2+ responses to sub-picomolar and nanomolar PACAP in pancreatic beta-cells are mediated by VPAC2 and PAC1 receptors. Regul Pept 123:147–153PubMedCrossRefGoogle Scholar
  38. Zwetsloot CP, Caekebeke JF, Ferrari MD (1993) Lack of asymmetry of middle cerebral artery blood velocity in unilateral migraine. Stroke 24:1335–1338PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Arsalan U. Syed
    • 1
  • Masayo Koide
    • 1
  • Karen M. Braas
    • 2
  • Victor May
    • 1
    • 2
  • George C. Wellman
    • 1
    Email author
  1. 1.Department of PharmacologyUniversity of VermontBurlingtonUSA
  2. 2.Department of Neurological SciencesUniversity of Vermont College of MedicineBurlingtonUSA

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