Version May 2024
INTRODUCTION — Vasoactive intestinal polypeptide (VIP) is a neuropeptide that functions as a neuromodulator and neurotransmitter. It is a potent vasodilator, regulates smooth muscle activity, epithelial cell secretion, and blood flow in the gastrointestinal tract [1-3]. As a chemical messenger, it functions as a neurohormone and paracrine mediator, being released from nerve terminals and acting locally on receptor-bearing cells.
The VIP receptor is a member of a unique class of G protein-coupled receptors. These receptors share a significant degree of sequence homology (>50 percent), which distinguishes them from members of the rhodopsin/beta-adrenergic family (class I) [4]. (See "Peptide hormone signal transduction and regulation".)
MOLECULAR FORMS — Like other gastrointestinal peptides, vasoactive intestinal polypeptide (VIP) is synthesized as a precursor molecule of 170 amino acids containing a signal peptide of 22 amino acids, which is then cleaved to the active peptide of 28 amino acids [5,6]. The gene encoding this peptide resides on chromosome 6 [7]. Some studies have demonstrated local control of VIP gene expression as VIP mRNA does not always parallel the peptide product [8]. These data suggest regulation at the post-transcriptional stage may be essential for normal VIP secretion [8].
The VIP peptide is remarkably well conserved across species and is identical in human, cow, pig, rat, dog, and goat species [3]. Even across species, amino acid substitutions are conservative and usually do not result in changes in bioactivity. VIP shares 68 percent sequence homology with pituitary adenylyl cyclase-activating peptide (PACAP).
Alternative peptides derived from the VIP gene include peptide histidine isoleucine (PHI) [9], peptide histidine methionine [10,11], and peptide histidine valine [6]. Although the functional significance of these peptides is unclear, PHI is known to stimulate intestinal fluid secretion [12].
TISSUE DISTRIBUTION — Vasoactive intestinal polypeptide (VIP) is expressed in the peripheral/enteric and central nervous systems. It is primarily localized to neurons, although it is also produced by other cell types. More recent studies have demonstrated that VIP is produced by immunomodulatory T cells. Immunolocalization studies have demonstrated VIP in nerve fibers located in many organs, including the luminal gastrointestinal tract [13,14], respiratory airways [6], pancreas [15], sensory organs [16], and reproductive system [17]. Cloning of the VIP receptor has provided complementary information on the localization of the VIP receptor [16,18,19].
RECEPTORS — G protein-coupled receptors (GPCRs) have been grouped into subfamilies based upon their amino acid sequence. The secretin/vasoactive intestinal polypeptide (VIP) family of receptors (consisting of receptors for VIP, secretin, glucagon, calcitonin, parathyroid hormone, pituitary adenylyl cyclase-activating peptide [PACAP], and others) is structurally unique. Given the considerable overlap between VIP and PACAP receptor agonist binding, nomenclature for these receptors has been standardized [20].
There are two known VIP receptor types (vasoactive intestinal polypeptide receptor 1 [VPAC1] and vasoactive intestinal polypeptide receptor 2 [VPAC2]). Notably, the PACAP receptor (PAC1) also binds VIP, although with much lower affinity.
Class II GPCRs lack structural signature sequences present in the rhodopsin/ß-adrenergic receptor family (such as a DRY motif - Asp-Arg-Tyr - at the end of the third transmembrane spanning domain), which appear to be important in receptor coupling to G proteins. VIP binds to its specific heptahelical membrane receptor and activates the heterotrimeric G protein, Gs, leading to elevation of cellular cAMP levels. This second messenger begins the signaling cascade that initiates appropriate cell physiologic responses. (See "Peptide hormone signal transduction and regulation".)
The mechanisms for VIP receptor signal termination include receptor phosphorylation mediated by G protein-coupled receptor kinases. Interestingly, the mechanism for VIP receptor internalization is distinct from that used by prototypical Class I GPCRs. This observation suggests that novel proteins may be involved in its regulation.
VIP receptors and mRNA are found in various tissues in the gastrointestinal tract and brain. Receptors are abundant on smooth muscle of sphincters of the lower esophagus, ampulla of Vater, and rectum. In these locations, VIP regulates sphincter relaxation. VIP receptors on pancreatic acinar and duct cells and enteric mucosal cells mediate fluid secretion in these organs.
VIP RELEASE — As mentioned above, vasoactive intestinal polypeptide (VIP) was originally identified in the gastrointestinal tract and named for its potent vasodilatation [2]. It was subsequently recognized as a neurotransmitter in the central and peripheral nervous systems [21,22]. Because VIP is released from neurons, it is likely that the majority of measurable VIP in serum is of neuronal origin [23]. Serum VIP levels are low and do not appreciably change with a meal. In pathologic conditions, like pancreatic cholera (watery diarrhea-hypokalemia-achlorhydria, WDHA, or Verner-Morrison syndrome [24]), VIP levels can be extraordinarily high [25,26]. Although VIP-secreting tumors are rare, in adults, most VIPomas are found in the pancreas, however, in children the majority of VIP-secreting tumors are ganglioneuromas or ganglioneuroblastomas. (See "VIPoma: Clinical manifestations, diagnosis, and management".)
Because VIP is derived from a precursor peptide (see 'Molecular forms' above) it is released along with other peptides, including primarily peptide histidine isoleucine and/or peptide histidine methionine [27-29]. It is also released with enzymes of the nitric oxide (NO) synthesis cascade, specifically NO synthase in neurons of the myenteric plexus [30,31]. The physiologic mechanisms of this co-release are an active area of investigation [32].
VIP PHYSIOLOGY — Vasoactive intestinal polypeptide (VIP) is an important neurotransmitter throughout the central and peripheral nervous systems. Due to its wide distribution, VIP has effects on many organ systems (table 1) [21]. In particular, it:
●Stimulates gastrointestinal epithelial secretion [25,26] and absorption [33].
●Promotes fluid and bicarbonate secretion from bile duct cholangiocytes [34].
●Is a potent relaxer of smooth muscle, including the lower esophageal sphincter [35] and colon [36].
●Increases the growth of certain adenocarcinomas [37].
●Causes vasodilation.
●Exerts anti-inflammatory actions.
VIP, along with nitric oxide, is a primary component of the non-adrenergic non-cholinergic nerve transmission in the gut [38,39]. Gastrointestinal smooth muscle exhibits a basal tone, or sustained tension, which is generated by rhythmic depolarizations (also called slow waves) of the smooth muscle membrane. Contractions occur when the slow waves reach a threshold level for calcium entry through calcium channels [39]. VIP serves as an inhibitory transmitter of this rhythmic activity, causing membrane hyperpolarization and subsequent relaxation of gastrointestinal smooth muscle [39,40]. In the intestine, VIP neurons project not only to other enteric neurons but also to muscle and epithelial cells, where they regulate circular muscle and epithelial chloride secretion.
VIP is an important neuromodulator in sphincters of the gastrointestinal tract including the lower esophageal sphincter and sphincter of Oddi. In certain pathological conditions, such as achalasia and Hirschsprung disease, the lack of VIP innervation is believed to have a major role in defective esophageal relaxation and bowel dysmotility.
VIP has immunomodulatory properties [41,42]. It is produced by a population of Th2 lymphocytes and promotes Th2-type immune responses [43]. In antigen-primed CD4 T cells in vitro, VIP inhibits Th1 cytokines interferon gamma and IL-2. In macrophages and dendritic cells, VIP induces Th2 cytokines IL-4 and IL-5. In vivo, VIP administration increases the ratio of Th2/Th1 cells. VIP also downregulates TNF-alpha expression. Thus, VIP appears to regulate the balance between pro-inflammatory and anti-inflammatory influences by inducing the emergence of T-cell effectors [44]. As a result, VIP has endogenous anti-inflammatory activity. Beneficial effects of VIP have been demonstrated in animal models of arthritis, sepsis, and pancreatitis [45]. Considerable evidence suggests that VIP may participate in the pathogenesis of inflammatory bowel disease [46,47]. These effects are likely due to its anti-inflammatory effects, but VIP also appears to regulate intestinal epithelial barrier function through effects on tight junction proteins [48]. Although reports suggested that VIP could reduce the histopathological severity in an experimental model of colitis, these results have not been uniformly reproduced [49].
VIP has effects on pulmonary vasculature and may play a role in pulmonary arterial hypertension. VIP has been shown to relax pulmonary vascular smooth muscle and attenuate vasoconstriction induced by endothelin and other mediators [50]. These actions likely contribute to the observation that mice with targeted disruption of the VIP gene have a phenotype that is remarkably similar to spontaneous pulmonary arterial hypertension with vascular remodeling and lung inflammation [51]. The antiproliferative effects of VIP may limit pulmonary vascular remodeling, and VIP is being investigated as a possible treatment for pulmonary arterial hypertension [52].
Mice with targeted disruption of the VIP gene have a phenotype that is remarkably similar to spontaneous pulmonary arterial hypertension with vascular remodeling and lung inflammation [51]. Interestingly, these mice also have disturbances in circadian rhythm [53] as well as altered inflammatory responses [54].
VIP has potent vasodilatory effects on the vasculature of the head and neck, and elevated VIP levels have been found in the blood of patients with migraine headaches [55,56]. However, despite its direct vascular effects, VIP does not appear to induce migraine attacks [57].
VIP increases secretion of bombesin-like peptides, which are autocrine growth factors for small cell lung cancer. Therefore, it is possible that VIP could indirectly contribute to lung cancer growth [58].
VIP receptors 1 and 2 (VPAC1 and VPAC2) are expressed on a number of common cancers including lung, breast, and prostate. Understandably, VIP has prominent growth promoting effects on such cancers [59].
Pancreatic islet beta cells express VPAC1, VPAC2, and the pituitary adenylyl cyclase-activating peptide (PACAP) receptor (PAC1) and VIP knockout mice exhibit elevated plasma glucose levels, indicating that VIP may influence beta cell function [60].
CLINICAL IMPLICATIONS — One of the most common clinical uses of vasoactive intestinal polypeptide (VIP) is in the radioimmunoassay for serum VIP quantitation in the evaluation of chronic secretory or high-volume diarrhea [61]. Patients with a VIP-producing tumor usually present with voluminous diarrhea (ie, pancreatic cholera) [26,62]. In contrast, patients with small volume, infrequent diarrhea are unlikely to have a VIP-producing tumor. (See "VIPoma: Clinical manifestations, diagnosis, and management".)
VIP-secreting tumors, various pancreatic adenocarcinomas, and carcinoid tumors express VIP receptors. Thus, radionuclide imaging using radiolabeled VIP analogues has been used to locate and guide resection of these often difficult to find tumors [63-65]. Improved understanding about the receptors expressed by various tumors should permit improved localization for surgical resection and chemotherapy.
Vasoactive intestinal polypeptide receptor 1 (VPAC1) has been found in prostate cancer [66], and it has been proposed that VPAC1 cells shed into the urine could be used in prostate cancer diagnosis [67]. Some breast, lung, gastric, pancreas, colon, bladder, and central nervous system tumors express VPAC1, VPAC2, or the PACAP (PAC1) receptors and may contribute to cancer growth and differentiation [68].
Mast cell infiltration and VIP release has been associated with irritable bowel syndrome with diarrhea (IBS-D) [69]. Moreover, plasma VIP levels have been reported to be elevated in patients with irritable bowel syndrome (IBS) [70]. Interestingly, a population of mast cells express VPAC1 rendering them susceptible to VIP stimulation. It has been proposed that altered mast cell function may contribute to colonic mucosal barrier dysfunction in IBS [71]. Despite initial enthusiasm, it remains to be determined if circulating VIP levels can be used as a maker of IBS. This is particularly problematic since elevated VIP levels have also been reported in inflammatory bowel diseases including Crohn disease and ulcerative colitis [72]. Therefore, it seems unlikely that VIP measurements will have sufficient specificity to be clinically useful.
A deficiency of VIP-secreting neurons has been implicated in a number of disease states. As an example, patients with Hirschsprung's disease have a deficiency of VIP-containing ganglion cells in the colon [73]. Similarly, patients with achalasia have reduced VIP levels in smooth muscle of the distal esophagus [74]. Interestingly, sweat glands from patients with cystic fibrosis have reduced VIP-innervation [75].
Therapeutic uses of VIP or VIP analogues are being established. VIP has been used to treat pulmonary hypertension and sarcoidosis [76]. VIP has the advantage of targeting both the innate and adaptive immune systems and affecting a large number of proinflammatory chemokines and cytokines. A role has been suggested for treating acute and chronic inflammatory and autoimmune diseases, including septic shock, rheumatoid arthritis, multiple sclerosis, Crohn disease, diabetes and neurodegenerative diseases such as Parkinson’s disease [77]. A major limitation has been route of delivery because, as a peptide, VIP requires parenteral or nasal administration. It is also susceptible to rapid proteolytic degradation; therefore, strategies are being developed to extend its short half-life yet avoid undesirable side effects such as hypotension.
SUMMARY
●Vasoactive intestinal polypeptide (VIP) is a neuropeptide that functions as a neuromodulator and neurotransmitter. It is a potent vasodilator, regulates smooth muscle activity, epithelial cell secretion, and blood flow in the gastrointestinal tract. As a chemical messenger, it functions as a neurohormone and paracrine mediator. (See 'Introduction' above.)
●VIP is synthesized as a precursor molecule, which is then cleaved to the active peptide. (See 'Molecular forms' above.)
●VIP is expressed in the peripheral/enteric and central nervous systems. It is primarily localized to neurons, although it is also produced by other cell types including immunomodulatory T cells. (See 'Tissue distribution' above.)
●There are two known VIP receptor types (VIP type 1 and VIP type 2 receptors). VIP receptors and mRNA are found in various tissues in the gastrointestinal tract and brain. Receptors are abundant on smooth muscle of sphincters of the lower esophagus, ampulla of Vater, and rectum. In these locations, VIP regulates sphincter relaxation. VIP receptors on pancreatic acinar and duct cells and enteric mucosal cells mediate fluid secretion in these organs. (See 'Receptors' above.)
●VIP has effects on many organ systems. It stimulates gastrointestinal epithelial secretion and absorption, promotes fluid and bicarbonate secretion from bile duct cholangiocytes, relaxes smooth muscles, including the lower esophageal sphincter and colon, increases the growth of certain adenocarcinomas, causes vasodilation, and exerts anti-inflammatory actions. (See 'VIP physiology' above.)
●Patients with a VIP-producing tumor usually present with voluminous diarrhea (ie, pancreatic cholera). Clinical uses of VIP include radioimmunoassay for serum VIP quantitation in the evaluation of chronic secretory or high volume diarrhea.
Radionuclide imaging has been used to locate and guide resection of VIP-secreting tumors, pancreatic adenocarcinomas, and carcinoid tumors that express VIP receptors. (See 'Clinical implications' above.)
●Future therapeutic uses of VIP or VIP analogues may include treating acute and chronic inflammatory and autoimmune diseases, including septic shock, rheumatoid arthritis, multiple sclerosis, Parkinson disease, Crohn disease, and diabetes. (See 'Clinical implications' above.)
آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟
