Peptide Vasoattivo Intestinale (VIP)

Il Peptide Vasoattivo Intestinale (VIP, Vasoactive Intestinal Peptide), è un enterormone, costituito da 28 aminoacidi, isolato nel 1970 da Said e Mutt   per estrazione dal duodeno di maiale. E’   secreto principalmente nell’intestino e pancreas  ma anche in altri tessuti come le cellule nervose e gli assoni neuronali, tiroide, midollare del surrene, cuore, ipotalamo, circolo portale ed adenoipofisi. Il gene codificante la sintesi di questo peptide risiede sul cromosoma 6q24 (1-3,51-57). I valori sierici di VIP >75 pg/ml indicano la presenza di un tumore entero-pancreatico che causa ipersecrezione di VIP; valori >200 pg/ml invece sono suggestivi di tumori VIP secernenti  chiamati VIPoma o Apudomi. Questi tumori sono maligni nell’80% dei casi e quasi sempre la diagnosi è quasi sempre tardiva quando ormai si sono creati focolai diffusi di metastasi. (41-47).

Il VIP, rilasciato dalle terminazioni nervose, agisce localmente legandosi a specifici recettori cellulari: 2GPCR (VPAC1 e VPAC2). L’attivazione di questi recettori induce aumento della concentrazione di Ca++ intracellulare, stimolazione dell’adenilciclasi e aumento della sintesi di c-AMP (4-7).

Il VIP è il peptide che più frequentemente si riscontra nel cervello − soprattutto nella corteccia cerebrale, nel lobo frontale e nell’ipotalamo − e per questo a volte ascritto alla classe dei neurotrasmettitori peptidici. Nella regione dei nuclei soprachiasmatici (SCN) cerebrali svolgono un ruolo di modulazione sul “pacemaker circadiano primario”  localizzato nella regione.

A livello ipotalamico, largamente presente nelle terminazioni neuronali ipotalamiche e nel circolo portale, induce la secrezione di prolattina (4-7). 

Il VIP è sintetizzato anche dalle cellule immunitarie che esprimono i recettori VIP ed esprime un’azione immunomodulante sui processi flogistici (8-13).

Il VIP possiede una vasta gamma di azioni: la più nota è una potente azione vasodilatatrice mediante rilasciamento della muscolatura liscia  vascolare, azione inotropa e cronotropa positiva, stimola la secrezione di acqua ed elettroliti intestinali, inibisce la secrezione dei succhi gastrici acidi e di gastrina: A livello pancreatico induce secrezione di insulina, glucagone e dei succhi pancreatici contenenti gli enzimi litici. Induce lipolisi e glicogenolisi. A livello vaginale svolge un ruolo preminente nel meccanismo della vasocongestione sessuale e lubrificazione (wetness) (11-22,50). Riduce incidenza e severità dell’artrite reumatoide con downregulation delle componenti flogistiche e immunitarie della patologia (23).

VIP e GESTOSI IPERTENSIVA:  è stato riscontrato un gene per un recettore ad elevata affinità per il VIP nei tessuti placentari. In queste cellule, il VIP, in sinergia con prostaciclina (PGI2) e nitrossido  (NO),  attiva l’adenilciclasi e modula la vasodilatazione arteriolare, il processo di invasione trofoblastica, placentazione e la sintesi di hCG attraverso la via del cAMP. Recentemente è stata dimostrata l’espressione di mRNA per il VIP da parte della placenta umana e la localizzazione del peptide nel citotrofoblasto e nel sinciziotrofoblasto (23-36). 

Il VIP inoltre facilita l’individuazione di alcuni apudomi (tumori neuroendocrini del pancreas) che secernono grande quantità di VIP  clinicamente caratterizzati da intensa diarrea, perdita di liquidi e di potassio: WDHA syndrome (Watery Diarrhea, Hypokalemia, and Achlorhydria) o S. di Verner-Morrison o colera pancreatico (34-48). 

Nel maschio il VIP rallenta l’invecchiamento testicolare e facilita la secrezione di FSH e testosterone (49).

References:

1.  Said SI, Giachetti A, Nicosia S. Adv Biochem Psychopharmacol. 1980; 22:75-82. 
2. Fahrenkrug J, Emson PC. Br Med Bull. 1982 Sep; 38(3):265-70.
3. Gozes I, Nakai H, Byers M, Avidor R, Weinstein Y, Shani Y, Shows TB: Sequential expression in the nervous system of c-myb and VIP genes, located in human chromosomal region 6q24. Somat Cell Mol Genet. 1987;13(4):305.
4. Gourdji D. et al: Vasoactive intestinal peptide (VIP) stimulates prolactin (PRL) release and cAMP production in a rat pituitary cell line (GH3/B6). Additive effects of VIP and TRH on PRL release. FEBS letter 1979;104,1:165-168.
5. Gozes I, Shani Y, Rostène WH. Developmental expression of the VIP-gene in brain and intestine. Brain Res 1987; 388:137.
6. Linder S, Barkhem T, Norberg A, et al. Structure and expression of the gene encoding the vasoactive intestinal peptide precursor. Proc Natl Acad Sci U S A 1987; 84:605.
7. Kulick R, Chaiseha Y, Kang S, Rozenboim I, El Halawani M (2005). “The relative importance of vasoactive intestinal peptide and peptide histidine isoleucine as physiological regulators of prolactin in the domestic turkey”. Gen Comp Endocrinol 142 (3): 267–73.
8. Yasui A, Naruse S, Yanaihara C, et al. Corelease of PHI and VIP by vagal stimulation in the dog. Am J Physiol 1987; 253:G13.
9. Ghiglione M, Christofides ND, Yiangou Y, et al. PHI stimulates intestinal fluid secretion. Neuropeptides 1982; 3:79.
10. Vasoactive intestinal peptide: a neuropeptide with pleiotropic immune functions. Delgado M, Ganea D. Amino Acids. 2013 Jul; 45(1):25-39. Epub 2011 Dec 3.
11. Pozo D et al: Immunobiology of vasoactive intestinal peptide (VIP)  Trends in Immunoloy Volume 21, Issue 1, p7–11, 1 January 2000
12. Pozo D, Gonzalez-Rey E, Chorny A, et al. Tuning immune tolerance with vasoactive intestinal peptide: a new therapeutic approach for immune disorders. Peptides 2007; 28:1833.
13. Pozo D et al: Trends in Immunology: Immunobiology of vasoactive intestinal peptide (VIP). Trend in Immunology 2000;21,1: 7-11
14. Novel concepts of neuropeptide-based drug therapy: vasoactive intestinal polypeptide and its receptors. Groneberg DA, Rabe KF, Fischer A. Eur J Pharmacol. 2006 Mar 8; 533(1-3):182-94. Epub 2006 Feb 10.
15. Vasoactive intestinal peptide: a neuropeptide with pleiotropic immune functions. Delgado M, Ganea D. Amino Acids. 2013 Jul; 45(1):25-39. Epub 2011 Dec 3. 
16. L. Battista, F. Trezza, A. Vitelli, L.O. Scaldarella, A.E. Pareto, R. Borrelli, A. Tolino: “Fattori angiogenetici e peptidi vasoattivi nella preeclampsia e nel ritardo di crescita intrauterino”.Giorn. It. Ost. Gin. 2011;Vol. XXXIII – n. 1
17. Khan KS, Wojdyla D, Say L, et al. WHO analysis of causes of maternal death: a systematic review. Lancet 2006;367: 1066-74.
18. Montan S, Sjoberg NO, Svenningsen N. Hypertension in pregnancy – fetal and infant outcome: a cohort study. Clin Exp Hypertens – Part B Hypertens Pregnancy 1987;6:337-48.
19. Klauber N, Rohan RM, Flynn E, D’Amato RJ. Critical components of the female reproductive pathway are suppressed by the angiogenesis inhibitor AGM-1470. Nat Med 1997;3: 443-446.
20. Torry RJ, Schwartz JS, Torry DS. Vascularization of the placenta. In Cardiovascular Molecular Morphogenesis: Assembly of the Vasculature and its Regulation, RJ Tomanek (ed.), New York, NY, Springer-Verlag, 2002.
21.  Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. Lancet 2005;365:785-99.Bloom SR, Bryant MG, Polak JM. Proceedings: Distribution of gut hormones. Gut. 1975 Oct;16(10):821–821. [PMC free article] [PubMed]
22. Bloom SR, Mitchell SJ, Greenberg GR, Christofides N, Domschke W, Domschke S, Mitznegg P, Demling L. Release of VIP, secretin and motilin after duodenal acidification in man. Acta Hepatogastroenterol (Stuttg) 1978 Oct;25(5):365–368. 
23. Bloom SR, Polak JM, Pearse AG. Vasoactive intestinal peptide and watery-diarrhoea syndrome. Lancet. 1973 Jul 7;2(7819):14–16.
24. Bryant MG, Polak MM, Modlin I, Bloom SR, Albuquerque RH, Pearse AG. Possible dual role for vasoactive intestinal peptide as gastrointestinal hormone and neurotransmitter substance. Lancet. 1976 May 8;1(7967):991–993. 
25. Buffa R, Capella C, Solcia E, Frigerio B, Said SI. Vasoactive intestinal peptide (VIP) cells in the pancrease and gastro-intestinal mucosa. An immunohistochemical and ultrastructural study. Histochemistry. 1977 Jan 24;50(3):217–227. 
26. Delgado, M., Abad, C., Martinez, C., Leceta, J., Gomariz, R. P. Vasoactive intestinal peptide prevents experimental arthritis by downregulating both autoimmune and inflammatory components of the disease. Nature Med. 7: 563-568, 2001. [PubMed: 11329057, related citations] [Full Text]                                                                                                                 
27. Ebeid AM, Murray P, Soeters PB, Fischer JE. Release of VIP by calcium stimulation. Am J Surg. 1977 Jan;133(1):140–144. [PubMed]
28. Frandsen EK, Moody AJ. Lipolytic action of a newly isolated vasoactive intestinal polypeptide. Horm Metab Res. 1973 May;5(3):196–199. 
29. Giachetti A, Said SI, Reynolds RC, Koniges FC. Vasoactive intestinal polypeptide in brain: localization in and release from isolated nerve terminals. Proc Natl Acad Sci U S A. 1977 Aug;74(8):3424–3428. [PMC free article] [PubMed]
30. Grossman MI. Candidate hormones of the gut. I. Introduction. Gastroenterology. 1974 Oct;67(4):730–731. [PubMed]
31. Kerins C, Said SI. Hyperglycemic and glycogenolytic effects of vasoactive intestinal polypeptide. Proc Soc Exp Biol Med. 1973 Mar;142(3):1014–1017. 
32. Larsson LI, Edvinsson L, Fahrenkrug J, Håkanson R, Owman C, Schaffalitzky de Muckadell O, Sundler F. Immunohistochemical localization of a vasodilatory polypeptide (VIP) in cerebrovascular nerves. Brain Res. 1976 Aug 27;113(2):400–404. 
33. Larsson LI, Fahrenkrug J, Schaffalitzky De Muckadell O, Sundler F, Håkanson R, Rehfeld JR. Localization of vasoactive intestinal polypeptide (VIP) to central and peripheral neurons. Proc Natl Acad Sci U S A. 1976 Sep;73(9):3197–3200. [PMC free article] [PubMed]
34. Mitchell SJ, Bloom SR. Measurement of fasting and postprandial plasma VIP in man. Gut. 1978 Nov;19(11):1043–1048. [PMC free article] [PubMed]
35. Polak JM, Pearse AG, Garaud JC, Bloom SR. Cellular localization of a vasoactive intestinal peptide in the mammalian and avian gastrointestinal tract. Gut. 1974 Sep;15(9):720–724. [PMC free article] [PubMed]
36. Said SI, Faloona GR. Elevated plasma and tissue levels of vasoactive intestinal polypeptide in the watery-diarrhea syndrome due to pancreatic, bronchogenic and other tumors. N Engl J Med. 1975 Jul 24;293(4):155–160. 
37. Said SI, Mutt V. Potent peripheral and splanchnic vasodilator peptide from normal gut. Nature. 1970 Feb 28;225(5235):863–864. 
38. Said SI, Mutt V. Polypeptide with broad biological activity: isolation from small intestine. Science. 1970 Sep 18;169(3951):1217–1218.
39. Said SI, Mutt V. Isolation from porcine-intestinal wall of a vasoactive octacosapeptide related to secretin and to glucagon. Eur J Biochem. 1972 Jul 13;28(2):199–204.
40. Said SI, Rosenberg RN. Vasoactive intestinal polypeptide: abundant immunoreactivity in neural cell lines and normal nervous tissue. Science. 1976 May 28;192(4242):907–908.
41. Schaffalitzky de Muckadell OB, Fahrenkrug J, Holst JJ. Release of vasoactive intestinal polypeptide (VIP) by electric stimulation of the vagal nerves. Gastroenterology. 1977 Feb;72(2):373–375. 
42. van Noorden S, Polak JM, Bloom SR, Bryant MG. Vasoactive intestinal polypeptide in the pituitary pars nervosa. Neuropathol Appl Neurobiol. 1979 Mar-Apr;5(2):149–153.
43. Ghaferi AA, Chojnacki KA, Long WD, et al: Pancreatic VIPomas: subject review and one institutional experience. J Gastrointest Surg 2008 Feb;12(2):382-393
44. Soga J, Yakuwa Y: Vipoma/diarrheogenic syndrome: a statistical evaluation of 241 reported cases. J Exp Clin Cancer Res. 1998 Dec;17(4):389-400
45. Smith SL, Branton SA, Avino AJ, et al: Vasoactive intestinal polypeptide secreting islet cell tumors: a 15-year experience and review of the literature. Surgery 1998 Dec;124(6):1050-1055 (Review)
46. Batcher E, Madaj P, Gianoukakis AG. Pancreatic neuroendocrine tumors. Endocr Res. 2011. 36(1):35-43. [Medline].
47. Alvite-Canosa M, Alonso-Fernández L, Seoane-López M, Pérz-Grobas J, Berdeal-Díaz M, Carral-Freire M, et al. Benign pancreatic vipoma. Rev Esp Enferm Dig. 2011 Mar. 103(4):224-5. [Medline].
48. Strosberg JR, Cheema A, Weber J, Han G, Coppola D, Kvols LK. Prognostic validity of a novel American Joint Committee on Cancer Staging Classification for pancreatic neuroendocrine tumors. J Clin Oncol. 2011 Aug 1. 29(22):3044-9. [Medline].
49. Verner JV, Morrison AB. Islet cell tumor and a syndrome of refractory watery diarrhea and hypokalemia. Am J Med. 1958 Sep. 25(3):374-80. [Medline].
50. Lacombe A et al: Rôle du peptide vasoactif intestinal (VIP) dans la stéroïdogenèse et le vieillissement testiculaire. Andrologie June 2007, 17:123
51. Ottesen B1, Pedersen B, Nielsen J, Dalgaard D, Wagner G, Fahrenkrug J. Vasoactive intestinal polypeptide (VIP) provokes vaginal lubrication in normal women. Peptides.1987 Sep-Oct;8(5):797-800.Said SI, Mutt V. Polypeptide with broad biological activity: isolation from small intestine. Science 1970; 169:1217.
52. Said SI, Mutt V. Potent peripheral and splanchnic vasodilator peptide from normal gut. Nature 1970; 225:863.
53. Dockray GJ. Vasoactive intestinal polypeptide and related peptides. In: Gut Hormones: Biochemistry and Physiology, 1st ed, Walsh JH, Dockray GJ (Eds), Raven Press, New York 1994. p.447.
54. Birnbaumer M. Mutations and diseases of G protein coupled receptors. J Recept Signal Transduct Res 1995; 15:131.
55. Linder S, Barkhem T, Norberg A, et al. Structure and expression of the gene encoding the vasoactive intestinal peptide precursor. Proc Natl Acad Sci U S A 1987; 84:605.
56. Maggi CA, Giachetti A, Dey RD, Said SI. Neuropeptides as regulators of airway function: vasoactive intestinal peptide and the tachykinins. Physiol Rev 1995; 75:277.
57. Gozes I, Nakai H, Byers M, et al. Sequential expression in the nervous system of c-myb and VIP genes, located in human chromosomal region 6q24. Somat Cell Mol Genet 1987; 13:305.
58. Gozes I, Shani Y, Rostène WH. Developmental expression of the VIP-gene in brain and intestine. Brain Res 1987; 388:137.