Background: Pituitary adenylate cyclase-activating polypeptide (PACAP) is a multifunctional neuropeptide in the VIP/secretin/glucagon peptide superfamily. Two active forms, PACAP1-38 and PACAP1-27, act through G protein-coupled receptors, the PAC1 and VPAC1/2 receptors. Effects of PACAP include potent vasomotor activity. Vasomotor activity and organ-specific vasomotor effects of PACAP-deficient mice have not yet been investigated; thus, the assessment of its physiological importance in vasomotor functions is still missing. We hypothesized that backup mechanisms exist to maintain PACAP pathway activity in PACAP knockout (KO) mice. Thus, we investigated the vasomotor effects of exogenous vasoactive intestinal peptide (VIP) and PACAP polypeptides in PACAP wild-type (WT) and PACAP-deficient (KO) male mice. Methods: Carotid and femoral arteries were isolated from 8- to 12-week-old male WT and PACAP-KO mice. Vasomotor responses were measured with isometric myography. Results: In the arteries of WT mice the peptides induced relaxations, which were significantly greater to PACAP1-38 than to PACAP1-27 and VIP. In KO mice, PACAP1-38 did not elicit relaxation, whereas PACAP1-27 and VIP elicited significantly greater relaxation in KO mice than in WT mice. The specific PAC1R and VPAC1R antagonist completely blocked the PACAP-induced relaxations. Conclusion: Our data suggest that in PACAP deficiency, backup mechanisms maintain arterial relaxations to polypeptides, indicating an important physiological role for the PACAP pathway in the regulation of vascular tone.

Vaudry D, Falluel-Morel A, Bourgault S, Basille M, Burel D, Wurtz O, Fournier A, Chow BK, Hashimoto H, Galas L, Vaudry H: Pituitary adenylate cyclase-activating polypeptide and its receptors: 20 years after the discovery. Pharmacol Rev 2009;61:283-357.
Broyart JP, Dupont C, Laburthe M, Rosselin G: Characterization of vasoactive intestinal peptide receptors in human colonic epithelial cells. J Clin Endocrinol Metab 1981;52:715-721.
Campbell RM, Scanes CG: Evolution of the growth hormone-releasing factor (GRF) family of peptides. Growth Regul 1992;2:175-191.
Segre GV, Goldring SR: Receptors for secretin, calcitonin, parathyroid hormone (PTH)/PTH-related peptide, vasoactive intestinal peptide, glucagonlike peptide 1, growth hormone-releasing hormone, and glucagon belong to a newly discovered G-protein-linked receptor family. Trends Endocrinol Metab 1993;4:309-314.
Laburthe M, Couvineau A: Molecular pharmacology and structure of VPAC receptors for VIP and PACAP. Regul Pept 2002;108:165-173.
Laburthe M, Couvineau A, Tan V: Class II G protein-coupled receptors for VIP and PACAP: structure, models of activation and pharmacology. Peptides 2007;28:1631-1639.
Lutz EM, MacKenzie CJ, Johnson M, West K, Morrow JA, Harmar AJ, Mitchell R: Domains determining agonist selectivity in chimaeric VIP2 (VPAC2)/PACAP (PAC1) receptors. Br J Pharmacol 1999;128:934-940.
Köves K, Arimura A, Görcs TG, Somogyvári-Vigh A: Comparative distribution of immunoreactive pituitary adenylate cyclase activating polypeptide and vasoactive intestinal polypeptide in rat forebrain. Neuroendocrinology 1991;54:159-169.
Légrádi G, Shioda S, Arimura A: Pituitary adenylate cyclase-activating polypeptide-like immunoreactivity in autonomic regulatory areas of the rat medulla oblongata. Neurosci Lett 1994;176:193-196.
Baun M, Hay-Schmidt A, Edvinsson L, Olesen J, Jansen-Olesen I: Pharmacological characterization and expression of VIP and PACAP receptors in isolated cranial arteries of the rat. Eur J Pharmacol 2011;670:186-194.
Chartrel N, Tonon MC, Vaudry H, Conlon JM: Primary structure of frog pituitary adenylate cyclase-activating polypeptide (PACAP) and effects of ovine PACAP on frog pituitary. Endocrinology 1991;129:3367-3371.
Hoyle CH: Neuropeptide families: evolutionary perspectives. Regul Pept 1998;73:1-33.
Sherwood NM, Krueckl SL, McRory JE: The origin and function of the pituitary adenylate cyclase-activating polypeptide (PACAP)/glucagon superfamily. Endocr Rev 2000;21:619-670.
Banki E, Sosnowska D, Tucsek Z, Gautam T, Toth P, Tarantini S, Tamas A, Helyes Z, Reglodi D, Sonntag WE, Csiszar A, Ungvari Z: Age-related decline of autocrine pituitary adenylate cyclase-activating polypeptide impairs angiogenic capacity of rat cerebromicrovascular endothelial cells. J Gerontol A Biol Sci Med Sci 2015;70:665-674.
Minkes RK, McMahon TJ, Higuera TR, Murphy WA, Coy DH, Kadowitz PJ: Analysis of systemic and pulmonary vascular responses to PACAP and VIP: role of adrenal catecholamines. Am J Physiol 1992;263:H1659-H1669.
Moller K, Sundler F: Expression of pituitary adenylate cyclase activating peptide (PACAP) and PACAP type I receptors in the rat adrenal medulla. Regul Pept 1996;63:129-139.
Nandha KA, Benito-Orfila MA, Smith DM, Ghatei MA, Bloom SR: Action of pituitary adenylate cyclase-activating polypeptide and vasoactive intestinal polypeptide on the rat vascular system: effects on blood pressure and receptor binding. J Endocrinol 1991;129: 69-73.
Ross-Ascuitto NT, Ascuitto RJ, Ramage D, Kydon DW, Coy DH, Kadowitz PJ: Pituitary adenylate cyclase activating polypeptide: a neuropeptide with potent inotropic and coronary vasodilatory effects in neonatal pig hearts. Pediatr Res 1993;34:323-328.
Ishizuka Y, Kashimoto K, Mochizuki T, Sato K, Ohshima K, Yanaihara N: Cardiovascular and respiratory actions of pituitary adenylate cyclase-activating polypeptides. Regul Pept 1992;40:29-39.
Markovics A, Kormos V, Gaszner B, Lashgarara A, Szoke E, Sandor K, Szabadfi K, Tuka B, Tajti J, Szolcsanyi J, Pinter E, Hashimoto H, Kun J, Reglodi D, Helyes Z: Pituitary adenylate cyclase-activating polypeptide plays a key role in nitroglycerol-induced trigeminovascular activation in mice. Neurobiol Dis 2012;45:633-644.
Anzai M, Suzuki Y, Takayasu M, Kajita Y, Mori Y, Seki Y, Saito K, Shibuya M: Vasorelaxant effect of PACAP-27 on canine cerebral arteries and rat intracerebral arterioles. Eur J Pharmacol 1995;285:173-179.
Erdling A, Sheykhzade M, Maddahi A, Bari F, Edvinsson L: VIP/PACAP receptors in cerebral arteries of rat: characterization, localization and relation to intracellular calcium. Neuropeptides 2013;47:85-92.
Vamos Z, Ivic I, Cseplo P, Toth G, Tamas A, Reglodi D, Koller A: Pituitary adenylate cyclase-activating polypeptide (PACAP) induces relaxations of peripheral and cerebral arteries, which are differentially impaired by aging. J Mol Neurosci 2014;54:535-542.
Cheng DY, McMahon TJ, Dewitt BJ, Carroll GC, Lee SS, Murphy WA, Bitar KG, Coy DH, Kadowitz PJ: Comparison of responses to pituitary adenylate cyclase activating peptides 38 and 27 in the pulmonary vascular bed of the cat. Eur J Pharmacol 1993;243:79-82.
Wilson AJ, Warren JB: Adenylate cyclase-mediated vascular responses of rabbit aorta, mesenteric artery and skin microcirculation. Br J Pharmacol 1993;110:633-638.
Wallengren J: Vasoactive peptides in the skin. J Investig Dermatol Symp Proc 1997;2:49-55.
Miyata A, Sato K, Hino J, Tamakawa H, Matsuo H, Kangawa K: Rat aortic smooth-muscle cell proliferation is bidirectionally regulated in a cell cycle-dependent manner via PACAP/VIP type 2 receptor. Ann NY Acad Sci 1998;865:73-81.
Cardell LO, Uddman R, Luts A, Sundler F: Pituitary adenylate cyclase activating peptide (PACAP) in guinea-pig lung: distribution and dilatory effects. Regul Pept 1991;36:379-390.
Harmar AJ, Sheward WJ, Morrison CF, Waser B, Gugger M, Reubi JC: Distribution of the VPAC2 receptor in peripheral tissues of the mouse. Endocrinology 2004;145:1203-1210.
Fahrenkrug J, Hannibal J, Tams J, Georg B: Immunohistochemical localization of the VIP1 receptor (VPAC1R) in rat cerebral blood vessels: relation to PACAP and VIP containing nerves. J Cereb Blood Flow Metab 2000;20:1205-1214.
Hashimoto H, Shintani N, Tanaka K, Mori W, Hirose M, Matsuda T, Sakaue M, Miyazaki J, Niwa H, Tashiro F, Yamamoto K, Koga K, Tomimoto S, Kunugi A, Suetake S, Baba A: Altered psychomotor behaviors in mice lacking pituitary adenylate cyclase-activating polypeptide (PACAP). Proc Natl Acad Sci USA 2001;98:13355-13360.
Reglodi D, Kiss P, Szabadfi K, Atlasz T, Gabriel R, Horvath G, Szakaly P, Sandor B, Lubics A, Laszlo E, Farkas J, Matkovits A, Brubel R, Hashimoto H, Ferencz A, Vincze A, Helyes Z, Welke L, Lakatos A, Tamas A: PACAP is an endogenous protective factor - insights from PACAP-deficient mice. J Mol Neurosci 2012;48:482-492.
Mori H, Nakamachi T, Ohtaki H, Yofu S, Sato A, Endo K, Iso Y, Suzuki H, Takeyama Y, Shintani N, Hashimoto H, Baba A, Shioda S: Cardioprotective effect of endogenous pituitary adenylate cyclase-activating polypeptide on doxorubicin-induced cardiomyopathy in mice. Circ J 2010;74:1183-1190.
Józsa R, Hollósy T, Tamas A, Tóth G, Lengvári I, Reglodi D: Pituitary adenylate cyclase activating polypeptide plays a role in olfactory memory formation in chicken. Peptides 2005;26:2344-2350.
Mulvany MJ, Halpern W: Contractile properties of small arterial resistance vessels in spontaneously hypertensive and normotensive rats. Circ Res 1977;41:19-26.
Ivic I, Vamos Z, Cseplo P, Koller A: From newborn to senescence morphological and functional remodeling leads to increased contractile capacity of arteries. J Gerontol A Biol Sci Med Sci 2017;72:481-488.
Tamas A, Reglodi D, Farkas O, Kovesdi E, Pal J, Povlishock JT, Schwarcz A, Czeiter E, Szanto Z, Doczi T, Buki A, Bukovics P: Effect of PACAP in central and peripheral nerve injuries. Int J Mol Sci 2012;13:8430-8448.
Huang M, Shirahase H, Rorstad OP: Comparative study of vascular relaxation and receptor binding by PACAP and VIP. Peptides 1993;14:755-762.
Syed AU, Koide M, Braas KM, May V, Wellman GC: Pituitary adenylate cyclase-activating polypeptide (PACAP) potently dilates middle meningeal arteries: implications for migraine. J Mol Neurosci 2012;48:574-583.
Chan KY, Baun M, de Vries R, van den Bogaerdt AJ, Dirven CM, Danser AH, Jansen-Olesen I, Olesen J, Villalón CM, MaassenVanDenBrink A, Gupta S: Pharmacological characterization of VIP and PACAP receptors in the human meningeal and coronary artery. Cephalalgia 2011;31:181-189.
Knutsson M, Edvinsson L: Distribution of mRNA for VIP and PACAP receptors in human cerebral arteries and cranial ganglia. Neuroreport 2002;13:507-509.
Otto C, Hein L, Brede M, Jahns R, Engelhardt S, Gröne HJ, Schütz G: Pulmonary hypertension and right heart failure in pituitary adenylate cyclase-activating polypeptide type I receptor-deficient mice. Circulation 2004;110:3245-3251.
DiCicco-Bloom E, Deutsch PJ, Maltzman J, Zhang J, Pintar JE, Zheng J, Friedman WF, Zhou X, Zaremba T: Autocrine expression and ontogenetic functions of the PACAP ligand/receptor system during sympathetic development. Dev Biol 2000;219:197-213.
Waschek JA, Lelievre V, Bravo DT, Nguyen T, Muller JM: Retinoic acid regulation of the VIP and PACAP autocrine ligand and receptor system in human neuroblastoma cell lines. Peptides 1997;18:835-841.
Hoover DB, Tompkins JD, Parsons RL: Differential activation of guinea pig intrinsic cardiac neurons by the PAC1 agonists maxadilan and pituitary adenylate cyclase-activating polypeptide 27 (PACAP27). J Pharmacol Exp Ther 2009;331:197-203.
Svensjö E, Saraiva EM, Amendola RS, Barja-Fidalgo C, Bozza MT, Lerner EA, Teixeira MM, Scharfstein J: Maxadilan, the Lutzomyia longipalpis vasodilator, drives plasma leakage via PAC1-CXCR1/2-pathway. Microvasc Res 2012;83:185-193.
Karacay B, O'Dorisio MS, Kasow K, Hollenback C, Krahe R: Expression and fine mapping of murine vasoactive intestinal peptide receptor 1. J Mol Neurosci 2001;17:311-324.
Rodríguez-Martínez MA, García-Cohen EC, Baena AB, González R, Salaíces M, Marín J: Contractile responses elicited by hydrogen peroxide in aorta from normotensive and hypertensive rats: endothelial modulation and mechanism involved. Br J Pharmacol 1998;125:1329-1335.
Miyata A, Arimura A, Dahl RR, Minamino N, Uehara A, Jiang L, Culler MD, Coy DH: Isolation of a novel 38 residue-hypothalamic polypeptide which stimulates adenylate cyclase in pituitary cells. Biochem Biophys Res Commun 1989;164:567-574.
Koide M, Syed AU, Braas KM, May V, Wellman GC: Pituitary adenylate cyclase activating polypeptide (PACAP) dilates cerebellar arteries through activation of large-conductance Ca2+-activated (BK) and ATP-sensitive (KATP) K+ channels. J Mol Neurosci 2014;54:443-450.
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