Vasoactive intestinal peptide

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Vasoactive intestinal peptide, also known as vasoactive intestinal polypeptide or VIP, is a peptide hormone that is vasoactive in the intestine. VIP is a peptide of 28 amino acid residues that belongs to a glucagon/secretin superfamily, the ligand of class II G protein–coupled receptors.[1] VIP is produced in many tissues of vertebrates including the gut, pancreas, and suprachiasmatic nuclei of the hypothalamus in the brain.[2][3][4] VIP stimulates contractility in the heart, causes vasodilation, increases glycogenolysis, lowers arterial blood pressure and relaxes the smooth muscle of trachea, stomach and gall bladder. In humans, the vasoactive intestinal peptide is encoded by the VIP gene.[5]

VIP has a half-life (t½) in the blood of about two minutes.[6]


The leading hypothesis of VIP function points to the neurons using VIP to communicate with specific postsynaptic targets to regulate circadian rhythm.[7] The depolarization of the VIP expressing neurons by light appears to cause the release of VIP and co-transmitters (including GABA) that can in turn, alter the properties of the next set of neurons with the activation of VPAC2. Another hypothesis supports VIP sending a paracrine signal from a distance rather than the adjacent postsynaptic neuron.[7]

In the body

VIP has an effect on several tissues:

With respect to the digestive system, VIP seems to induce smooth muscle relaxation (lower esophageal sphincter, stomach, gallbladder), stimulate secretion of water into pancreatic juice and bile, and cause inhibition of gastric acid secretion and absorption from the intestinal lumen.[8] Its role in the intestine is to greatly stimulate secretion of water and electrolytes,[9] as well as relaxation of enteric smooth muscle, dilating peripheral blood vessels, stimulating pancreatic bicarbonate secretion, and inhibiting gastrin-stimulated gastric acid secretion. These effects work together to increase motility.[10]It also has the function of stimulating pepsinogen secretion by chief cells.[11] It is also found in the heart and has significant effects on the cardiovascular system. It causes coronary vasodilation[8] as well as having a positive inotropic and chronotropic effect. Research is being performed to see if it may have a beneficial role in the treatment of heart failure. VIP provokes vaginal lubrication in normal women, doubling the total volume of lubrication produced.[12][13]

In the brain

It is also found in the brain and some autonomic nerves:

One region includes a specific area of the suprachiasmatic nuclei (SCN), the location of the 'master circadian pacemaker'.[14] See SCN and circadian rhythm below. VIP in the pituitary helps to regulate prolactin secretion; it stimulates prolactin release in the domestic turkey.[15] Additionally, the growth-hormone-releasing hormone (GH-RH) is a member of the VIP family and stimulates growth hormone secretion in the anterior pituitary gland.[16][17]


VIP innervates on both VPAC1 and VPAC2. When VIP binds to VPAC2 receptors, a G-alpha-mediated signalling cascade is triggered. In a number of systems, VIP binding activates adenyl cyclase activity leading to increases in cAMP and PKA. The PKA then activates other intracellular signaling pathways like the phosphorylation of CREB and other transcriptional factors. The mPer1 promoter has CRE domains and thus provides the mechanism for VIP to regulate the molecular clock itself. Then it will activate gene expression pathways such as Per1 and Per2 in circadian rhythm.[7]

In addition, GABA levels are connected to VIP in that they are co-released. Sparse GABAergic connections are thought to decrease synchronized firing.[7] While GABA controls the amplitude of SCN neuronal rhythms, it is not critical for maintaining synchrony. However, if GABA release is dynamic, it may mask or amplify synchronizing effects of VIP inappropriately.[7]

Circadian time is likely to affect the synapses rather than the organization of VIP circuits.[7]

File:Suprachiasmatic Nucleus.jpg
Suprachiasmatic nucleus is shown in green.

SCN and circadian rhythm

The SCN coordinates daily timekeeping in the body and VIP plays a key role in communication between individual brain cells within this region. At a cellular level, the SCN expresses different electrical activity in circadian time. Higher activity is observed during the day, while during night there is lower activity. This rhythm is thought to be important feature of SCN to synchronize with each other and control rhythmicity in other regions.[14]

VIP acts as a major synchronizing agent among SCN neurons and plays a role in synchronizing the SCN with light cues. The high concentration of VIP and VIP receptor containing neurons are primarily found in the ventrolateral aspect of the SCN, which is also located above the optic chiasm. The neurons in this area receive retinal information from the retinohypothalamic tract and then relay the environmental information to the SCN.[7] Further, VIP is also involved in synchronizing the timing of SCN function with the environmental light-dark cycle. Combined, these roles in the SCN make VIP a crucial component of the mammalian circadian timekeeping machinery.[7]

After finding evidence of VIP in the SCN, researchers began contemplating its role within the SCN and how it could affect circadian rhythm. The VIP also plays a pivotal role in modulating oscillations. Previous pharmacological research has established that VIP is needed for normal light-induced synchronization of the circadian systems. Application of VIP also phase shifts the circadian rhythm of vasopressin release and neural activity. The ability of the population to remain synchronized as well as the ability of single cells to generate oscillations is composed in VIP or VIP receptor deficient mice. While not highly studied, there is evidence that levels of VIP and its receptor may vary depending on each circadian oscillation.[7]

Signaling pathway

In SCN, there is an abundant amount of VPAC2. The presence of VPAC2 in ventrolateral side suggests that VIP signals can actually signal back to regulate VIP secreting cells. SCN has neural multiple pathways to control and modulate endocrine activity.[14][18]

VIP and vasopressin are both important for neurons to relay information to different targets and affect neuroendocrine function. They transmit information through such relay nuclei as the SPZ (subparaventricular zone), DMH (dorsomedial hypothalamic nucleus), MPOA (medial preoptic area) and PVN (paraventricular nucleus of hypothalamus).[14]

Social behavior

Ventromedial hypothalamus (VM), optic chiasm (OC), anterior pituitary (AP), and posterior pituitary (PP) are shown here.

VIP neurons located in the hypothalamus, specifically the dorsal anterior hypothalamus and ventromedial hypothalamus, have an effect on social behaviors in many species of vertebrates. Studies suggest that VIP cascades can be activated in the brain in response to a social situation that stimulates the areas of the brain that are known to regulate behavior. This social circuit includes many areas of the hypothalamus along with the amygdala and the ventral tegmental area. The production and release of the neuropeptide VIP is centralized in the hypothalamic and extrahypothalamic regions of the brain and from there it is able to modulate the release of prolactin secretion.[19] Once secreted from the pituitary gland, prolactin can increase many behaviors such as parental care and aggression. In certain species of birds with a knockout VIP gene there was an observable decrease in overall aggression over nesting territory.[20]


VIP is overproduced in VIPoma.[9]

In addition to VIPoma, VIP has a role in osteoarthritis (OA). While there is existing conflict in whether down-regulation or up-regulation of VIP contributes to OA, VIP has been shown to prevent cartilage damage in animals.[21]

See also


  1. Umetsu Y, Tenno T, Goda N, Shirakawa M, Ikegami T, Hiroaki H (May 2011). "Structural difference of vasoactive intestinal peptide in two distinct membrane-mimicking environments". Biochimica et Biophysica Acta. 1814 (5): 724–30. doi:10.1016/j.bbapap.2011.03.009. PMID 21439408.
  2. Juhász T, Helgadottir SL, Tamás A, Reglődi D, Zákány R (April 2015). "PACAP and VIP signaling in chondrogenesis and osteogenesis". Peptides. 66: 51–7. doi:10.1016/j.peptides.2015.02.001. PMID 25701761.
  3. Delgado M, Ganea D (July 2013). "Vasoactive intestinal peptide: a neuropeptide with pleiotropic immune functions". Amino Acids. 45 (1): 25–39. doi:10.1007/s00726-011-1184-8. PMC 3883350. PMID 22139413.
  4. Fahrenkrug J (2010-01-01). "VIP and PACAP". Results and Problems in Cell Differentiation. 50: 221–34. doi:10.1007/400_2009_24. PMID 19859678.
  5. Hahm SH, Eiden LE (December 1998). "Cis-regulatory elements controlling basal and inducible VIP gene transcription". Annals of the New York Academy of Sciences. 865: 10–26. doi:10.1111/j.1749-6632.1998.tb11158.x. PMID 9927992.
  6. Henning RJ, Sawmiller DR (January 2001). "Vasoactive intestinal peptide: cardiovascular effects". Cardiovascular Research. 49 (1): 27–37. doi:10.1016/s0008-6363(00)00229-7. PMID 11121793.
  7. 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 Vosko AM, Schroeder A, Loh DH, Colwell CS (2007). "Vasoactive intestinal peptide and the mammalian circadian system". General and Comparative Endocrinology. 152 (2–3): 165–75. doi:10.1016/j.ygcen.2007.04.018. PMC 1994114. PMID 17572414.
  8. 8.0 8.1 Bowen R (1999-01-24). "Vasoactive Intestinal Peptide". Pathophysiology of the Endocrine System: Gastrointestinal Hormones. Colorado State University. Retrieved 2009-02-06.
  9. 9.0 9.1 "Vasoactive intestinal polypeptide". General Practice Notebook. Retrieved 2009-02-06.
  10. Bergman RA, Afifi AK, Heidger PM. "Plate 6.111 Vasoactive Intestinal Polypeptide (VIP)". Atlas of Microscopic Anatomy: Section 6 - Nervous Tissue. Retrieved 2009-02-06.
  11. Sanders MJ, Amirian DA, Ayalon A, Soll AH (November 1983). "Regulation of pepsinogen release from canine chief cells in primary monolayer culture". The American Journal of Physiology. 245 (5 Pt 1): G641–6. PMID 6195927.
  12. Levin RJ (1991-01-01). "VIP, vagina, clitoral and periurethral glans--an update on human female genital arousal". Experimental and Clinical Endocrinology. 98 (2): 61–9. doi:10.1055/s-0029-1211102. PMID 1778234.
  13. Graf AH, Schiechl A, Hacker GW, Hauser-Kronberger C, Steiner H, Arimura A, Sundler F, Staudach A, Dietze O (February 1995). "Helospectin and pituitary adenylate cyclase activating polypeptide in the human vagina". Regulatory Peptides. 55 (3): 277–86. doi:10.1016/0167-0115(94)00116-f. PMID 7761627.
  14. 14.0 14.1 14.2 14.3 Achilly NP (June 2016). "Properties of VIP+ synapses in the suprachiasmatic nucleus highlight their role in circadian rhythm". Journal of Neurophysiology. 115 (6): 2701–4. doi:10.1152/jn.00393.2015. PMC 4922597. PMID 26581865.
  15. Kulick RS, Chaiseha Y, Kang SW, Rozenboim I, El Halawani ME (July 2005). "The relative importance of vasoactive intestinal peptide and peptide histidine isoleucine as physiological regulators of prolactin in the domestic turkey". General and Comparative Endocrinology. 142 (3): 267–73. doi:10.1016/j.ygcen.2004.12.024. PMID 15935152.
  16. Kiaris H, Chatzistamou I, Papavassiliou AG, Schally AV (August 2011). "Growth hormone-releasing hormone: not only a neurohormone". Trends in Endocrinology and Metabolism. 22 (8): 311–7. doi:10.1016/j.tem.2011.03.006. PMID 21530304.
  17. Steyn FJ, Tolle V, Chen C, Epelbaum J (March 2016). "Neuroendocrine Regulation of Growth Hormone Secretion". Comprehensive Physiology. 6 (2): 687–735. doi:10.1002/cphy.c150002. PMID 27065166.
  18. Maduna T, Lelievre V (December 2016). "Neuropeptides shaping the central nervous system development: Spatiotemporal actions of VIP and PACAP through complementary signaling pathways". Journal of Neuroscience Research. 94 (12): 1472–1487. doi:10.1002/jnr.23915. PMID 27717098.
  19. Kingsbury MA (December 2015). "New perspectives on vasoactive intestinal polypeptide as a widespread modulator of social behavior". Current Opinion in Behavioral Sciences. 6: 139–147. doi:10.1016/j.cobeha.2015.11.003. PMC 4743552. PMID 26858968.
  20. Kingsbury MA, Wilson LC (December 2016). "The Role of VIP in Social Behavior: Neural Hotspots for the Modulation of Affiliation, Aggression, and Parental Care". Integrative and Comparative Biology. 56 (6): 1238–1249. doi:10.1093/icb/icw122. PMC 5146713. PMID 27940615.
  21. Jiang W, Wang H, Li YS, Luo W (August 2016). "Role of vasoactive intestinal peptide in osteoarthritis". Journal of Biomedical Science. 23 (1): 63. doi:10.1186/s12929-016-0280-1. PMC 4995623. PMID 27553659.

Further reading

  • Watanabe J (1 January 2016). "Subchapter 18E - Vasoactive Intestinal Peptide". Handbook of Hormones. Academic Press: 150–e18E-10. doi:10.1016/b978-0-12-801028-0.00146-x.
  • Fahrenkrug J (2001). "Gut/brain peptides in the genital tract: VIP and PACAP". Scandinavian Journal of Clinical and Laboratory Investigation. Supplementum. 234: 35–9. PMID 11713978.
  • Delgado M, Pozo D, Ganea D (June 2004). "The significance of vasoactive intestinal peptide in immunomodulation". Pharmacological Reviews. 56 (2): 249–90. doi:10.1124/pr.56.2.7. PMID 15169929.
  • Conconi MT, Spinazzi R, Nussdorfer GG (2006). "Endogenous ligands of PACAP/VIP receptors in the autocrine-paracrine regulation of the adrenal gland". International Review of Cytology. 249: 1–51. doi:10.1016/S0074-7696(06)49001-X. ISBN 978-0-12-364653-8. PMID 16697281.
  • Hill JM (2007). "Vasoactive intestinal peptide in neurodevelopmental disorders: therapeutic potential". Current Pharmaceutical Design. 13 (11): 1079–89. doi:10.2174/138161207780618975. PMID 17430171.
  • Gonzalez-Rey E, Varela N, Chorny A, Delgado M (2007). "Therapeutical approaches of vasoactive intestinal peptide as a pleiotropic immunomodulator". Current Pharmaceutical Design. 13 (11): 1113–39. doi:10.2174/138161207780618966. PMID 17430175.
  • Glowa JR, Panlilio LV, Brenneman DE, Gozes I, Fridkin M, Hill JM (January 1992). "Learning impairment following intracerebral administration of the HIV envelope protein gp120 or a VIP antagonist". Brain Research. 570 (1–2): 49–53. doi:10.1016/0006-8993(92)90562-n. PMID 1617429.
  • Theriault Y, Boulanger Y, St-Pierre S (March 1991). "Structural determination of the vasoactive intestinal peptide by two-dimensional H-NMR spectroscopy". Biopolymers. 31 (4): 459–64. doi:10.1002/bip.360310411. PMID 1863695.
  • Gozes I, Giladi E, Shani Y (April 1987). "Vasoactive intestinal peptide gene: putative mechanism of information storage at the RNA level". Journal of Neurochemistry. 48 (4): 1136–41. doi:10.1111/j.1471-4159.1987.tb05638.x. PMID 2434617.
  • Yamagami T, Ohsawa K, Nishizawa M, Inoue C, Gotoh E, Yanaihara N, Yamamoto H, Okamoto H (1988). "Complete nucleotide sequence of human vasoactive intestinal peptide/PHM-27 gene and its inducible promoter". Annals of the New York Academy of Sciences. 527: 87–102. doi:10.1111/j.1749-6632.1988.tb26975.x. PMID 2839091.
  • DeLamarter JF, Buell GN, Kawashima E, Polak JM, Bloom SR (1985). "Vasoactive intestinal peptide: expression of the prohormone in bacterial cells". Peptides. 6 Suppl 1 (Suppl 1): 95–102. doi:10.1016/0196-9781(85)90016-6. PMID 2995945.
  • Linder S, Barkhem T, Norberg A, Persson H, Schalling M, Hökfelt T, Magnusson G (January 1987). "Structure and expression of the gene encoding the vasoactive intestinal peptide precursor". Proceedings of the National Academy of Sciences of the United States of America. 84 (2): 605–9. doi:10.1073/pnas.84.2.605. PMC 304259. PMID 3025882.
  • Gozes I, Bodner M, Shani Y, Fridkin M (1986). "Structure and expression of the vasoactive intestinal peptide (VIP) gene in a human tumor". Peptides. 7 Suppl 1 (Suppl 1): 1–6. doi:10.1016/0196-9781(86)90156-7. PMID 3748844.
  • Tsukada T, Horovitch SJ, Montminy MR, Mandel G, Goodman RH (August 1985). "Structure of the human vasoactive intestinal polypeptide gene". Dna. 4 (4): 293–300. doi:10.1089/dna.1985.4.293. PMID 3899557.
  • Heinz-Erian P, Dey RD, Flux M, Said SI (September 1985). "Deficient vasoactive intestinal peptide innervation in the sweat glands of cystic fibrosis patients". Science. 229 (4720): 1407–8. doi:10.1126/science.4035357. PMID 4035357.

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