VIP: Research Into Cellular Survival and Inflammation Models

Vasoactive intestinal peptide (VIP) is described as a peptide composed of 28 amino acids, originally discovered in 1970 and initially recognized for its potential to promote the widening of blood vessels (vasodilation). ⁽¹⁾ VIP is classified as part of the secretin/glucagon hormone superfamily, a group of related hormones involved in regulating various physiological functions. VIP appears to be extensively distributed throughout both the central and peripheral nervous systems, as well as in various tissues, including the tissues of the gastrointestinal system. VIP is posited to play key roles in regulating numerous physiological processes and may also contribute to pathological mechanisms.

This peptide is thought to affect a variety of functions, such as neuroendocrine communication, cell growth, immune system regulation, and the activity of both epithelial cells and neurons. The peptide may exert its biological functions through its potential interaction with two G-protein-coupled receptors, VPAC1 and VPAC2. These receptors are typically described as a part of the secretin receptor family. These receptors possibly mediate the range of VIP’s potential in the gastrointestinal tissues, including regulation of motility, secretion, vasodilation, and immune modulation. Studies posit that VPAC1 and VPAC2 may enable VIP to mediate overlapping but distinct actions, depending on their localization and relative expression in various tissues. ⁽¹⁾

Fig1 – VIP Chemical Structure⁽²⁾

 

Latest Research on Vasoactive Intestinal Peptide

VPAC1 Receptors

The interaction of VIP with VPAC1 may affect the function of the epithelial barrier in gastrointestinal tissues. Jayawardena et al. have studied VPAC1 in-depth and report that this appears to be a receptor primarily found in epithelial cells of gastrointestinal tissues and is especially abundant in the mucosal and submucosal cells of the colon.⁽³⁾ This specific localization indicates that VPAC1 may play a role in regulating various physiological processes, including ion transport, mucus secretion, and the maintenance of tight junctions, which are critical for the integrity of the epithelial barrier. This influence is likely mediated through VPAC1’s regulation of tight junction proteins, which might lead to alterations in epithelial permeability.

Tight junctions are key structures that control the passage of molecules through the paracellular space, and their modulation by VPAC1, suggests a role in maintaining or disrupting barrier integrity. In addition to its role in regulating barrier function, VPAC1 might also contribute to the activation of epithelial and mast cells. Mast cells, which are involved in immune responses, may be activated by signals that lead to the release of pro-inflammatory mediators. The involvement of VPAC1 in this process suggests it may influence inflammatory responses by modulating secretion pathways.

VPAC2 Receptors

Abad et al. have revealed that VPAC2 receptors may be present in vascular and smooth muscle tissues rather than in epithelial cells. This may lead to the hypothesis that VIP’s actions on intestinal contractility, vasodilation, and inflammation may be largely mediated through these receptors.⁽⁴⁾ VPAC2 receptors are predominantly found in smooth muscle tissues throughout the gastrointestinal tract. These receptors are thought to play a crucial role in VIP-induced relaxation of vascular smooth muscle, leading to vasodilation.

These receptors may also be upregulated in activated immune cells, such as macrophages and T helper cells, suggesting a role in regulating immune responses. By activating VPAC2, VIP is believed to downregulate proinflammatory responses mediated by Th1 and Th17 cells, contributing to its anti-inflammatory potential.

VIP and Inflammation

As mentioned, VIP appears to be produced by lymphocytes and other immune cells, possibly playing a role in modulating immune responses. According to multiple studies reviewed by Delgado et al., VIP may potentially exhibit anti-inflammatory properties, as it appears to inhibit the production of pro-inflammatory cytokines such as Tumor Necrosis Factor alpha (TNFα), Interferon gamma (IFNγ), Interleukin-6 (IL-6), and Interleukin-12 (IL-12). Simultaneously, VIP might support the production of anti-inflammatory cytokines like Interleukin-10 (IL-10) and Interleukin-1 receptor antagonist (IL-1Ra).

By interacting with its receptors—VPAC1 and VPAC2—VIP may influence the activity of transcription factors such as Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) and Activator Protein 1 (AP-1). This interaction might potentially lead to altered gene expression of inflammatory mediators. In experimental laboratory settings, VIP has been observed to possibly downregulate the production of chemokines, which are signaling proteins that attract immune cells, and adhesion molecules that facilitate cell attachment.

This downregulation might reduce the recruitment of inflammatory cells. These findings suggest that VIP might have the potential to modulate inflammatory responses. Additionally, VIP has been proposed to influence the balance between T helper cell type 1 (Th1) and type 2 (Th2) immune responses, possibly shifting the balance toward a Th2 phenotype. This potential shift might be relevant in research models of autoimmunity where Th1 responses are predominant. Delgado et al. also comments that the peptide appears to ameliorate “the deleterious effects of an experimental model of rheumatoid arthritis by downregulating both inflammatory and autoimmune components” in such models, suggesting the need for additional research. ⁽⁵⁾

VIP and Pancreatic Cells Survival

A study by Hou et al. proposes that VIP might support the process of insulin secretion by pancreatic cells through the cyclic adenosine monophosphate (cAMP) signaling cascade.⁽⁶⁾ It is hypothesized that VIP binds to the VPAC2 on pancreatic cells, which might activate the enzyme adenylate cyclase. This activation might lead to an increased conversion of adenosine triphosphate (ATP) into cAMP within the cell. Elevated levels of cAMP might then potentially activate protein kinase A (PKA) and exchange proteins directly activated by cAMP (Epac).

This may result in higher intracellular calcium concentrations and possibly promote insulin release. Furthermore, VIP was suggested to regulate the proliferation of pancreatic β-cells—the cells responsible for producing insulin.⁽⁶⁾ Specifically, Delgado et al. suggest that VIP might promote β-cell proliferation via the forkhead box M1 (FoxM1) pathway, a transcription factor important for cell cycle progression and cellular proliferation. Activation of this pathway might support β-cell proliferation and consequently increase insulin secretion.⁽⁵⁾

VIP and Nerve Cell Survival

Studies by Deng et al. suggest that VIP may have neuroprotective potential linked to its capacity to modulate inflammatory responses within the nervous system. VIP might inhibit the release of proinflammatory cytokines from activated microglial cells, which are the primary immune cells in the central nervous system. By potentially reducing inflammatory processes, VIP might indirectly protect neurons in models of neurodegenerative conditions.

VIP may influence the production of neurotrophic factors such as activity-dependent neurotrophic factor (ADNF) and activity-dependent neuroprotective protein (ADNP). These proteins are produced by astrocytes (star-shaped glial cells that support neurons) and are thought to contribute to neuronal survival. By influencing ADNF and ADNP levels, VIP may further exert a neuroprotective potential.⁽⁷⁾

VIP and Cardiomyocyte Survival

Studies by Duggan et al. suggest that increases in VIP levels in research models were associated with a substantial reduction in myocardial fibrosis relative to both initial baseline levels and controls.⁽⁸⁾ The mechanisms by which VIP may exert its antifibrotic action appear to involve the modulation of specific profibrotic mediators within heart cells. During the experimental period, while the expression of several profibrotic mediators increased, VIP infusion selectively reduced the messenger RNA expression of angiotensinogen (Agt) and angiotensin receptor type 1a (AT1a).

These components are part of the renin-angiotensin system, which is suggested to play a role in promoting fibrosis within cardiac tissue. By downregulating Agt and AT1a expression, VIP might inhibit the local renin-angiotensin system within heart cells, thereby reducing fibrotic activity. This suggests that VIP’s antifibrotic action might be mediated through interference with the renin-angiotensin pathway in cardiac tissue. Additionally, VIP is theorized to exert vasodilatory influence and a possible ability to support the contraction of cardiac muscular tissue (positive inotropic action). These mechanisms might contribute to its potential actions on heart cells by improving blood flow and cardiac function, which might further influence the fibrotic processes as previously suggested by Hou et al.⁽⁶⁾

VIP and Vascular Dilation

VIP potentially induces vasodilation through complex mechanisms involving nitric oxide (NO) and histamine pathways. VIP may stimulate the release of histamine from mast cells, which may lead to vasodilation via activation of histamine receptors, particularly the H1 isoform. This histamine-mediated vasodilation is associated with increased NO production, suggesting that NO might play a role in VIP’s vasodilatory actions.

Experimental observations by Wilkins et al. indicate that VIP-mediated vasodilation includes a NO-dependent component not entirely accounted for by H1 and H2 histamine receptor activation.⁽⁹⁾ This implies that VIP might directly stimulate NO production or interact with NO signaling pathways independently of histamine receptors. The inhibition of NO synthase has been indicated in research studies to contribute to the attenuation of VIP-induced vasodilation. This supports the notion that NO contributes to the vasodilatory process initiated by VIP.

The lack of action from H2-receptor inhibition on VIP-mediated vasodilation suggests that H2 receptors may not be significantly involved in this mechanism. VIP’s potential to induce vasodilation through both histamine-dependent and histamine-independent pathways highlights its complex role in vascular regulation. It is possible that VIP and NO interact synergistically to support vasodilation.

VIP and Intestinal Inflammation

VIP may influence both innate and adaptive immune responses within the gastrointestinal tract. Recent research by Sun et al. has explored its potential role in modulating intestinal barrier function and inflammation through its interaction with regulatory B cells (Bregs) and the anti-inflammatory IL-10. Indeed, researchers comment that “VIP plays a key role in protecting the colon epithelium from pathogenic bacteria” in experimental models, with Bregs playing a central role in its mechanisms. Bregs are a subset of immune B cells known for their ability to produce IL-10, which is crucial for maintaining immune homeostasis.

IL-10 from Bregs possibly suppresses excessive inflammatory responses by influencing T helper cell differentiation. Specifically, it may promote a shift towards a Th2 phenotype while inhibiting Th1 cytokine production, thereby contributing to the balance between Th1 and Th2 responses. This balance may play a potential role in controlling inflammation in the intestinal mucosa. Researchers employed murine models of colitis induced by dextran sulfate sodium (DSS) or trinitrobenzene sulfonic acid (TNBS), and following exposure to VIP, the peptide apparently alleviated signs of intestinal inflammation.⁽¹⁰⁾ VIP is posited to support IL-10 expression in Bregs, potentially by stabilizing IL-10 mRNA, which might amplify its anti-inflammatory potential.

 
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References:

1. Iwasaki M, Akiba Y, Kaunitz JD. Recent advances in vasoactive intestinal peptide physiology and pathophysiology: focus on the gastrointestinal system. F1000Res. 2019 Sep 12;8:F1000 Faculty Rev-1629. doi: 10.12688/f1000research.18039.1. PMID: 31559013; PMCID: PMC6743256.
2. VIP Chemical Structure – https://pubchem.ncbi.nlm.nih.gov/image/imgsrv.fcgi?cid=53314964&t=l
3. Jayawardena D, Guzman G, Gill RK, Alrefai WA, Onyuksel H, Dudeja PK. Expression and localization of VPAC1, the major receptor of vasoactive intestinal peptide along the length of the intestine. Am J Physiol Gastrointest Liver Physiol. 2017 Jul 1;313(1):G16-G25. doi: 10.1152/ajpgi.00081.2017. Epub 2017 Apr 6. PMID: 28385693; PMCID: PMC5538834.
4. Abad C, Tan YV. Immunomodulatory Roles of PACAP and VIP: Lessons from Knockout Mice. J Mol Neurosci. 2018 Sep;66(1):102-113. doi: 10.1007/s12031-018-1150-y. Epub 2018 Aug 13. PMID: 30105629.
5. Delgado M, Abad C, Martinez C, Juarranz MG, Arranz A, Gomariz RP, Leceta J. Vasoactive intestinal peptide in the immune system: potential therapeutic role in inflammatory and autoimmune diseases. J Mol Med (Berl). 2002 Jan;80(1):16-24. doi: 10.1007/s00109-001-0291-5. Epub 2001 Oct 17. PMID: 11862320.
6. Hou X, Yang D, Yang G, Li M, Zhang J, Zhang J, Zhang Y, Liu Y. Therapeutic potential of vasoactive intestinal peptide and its receptor VPAC2 in type 2 diabetes. Front Endocrinol (Lausanne). 2022 Sep 20;13:984198. doi: 10.3389/fendo.2022.984198. PMID: 36204104; PMCID: PMC9531956.
7. Deng G, Jin L. The effects of vasoactive intestinal peptide in neurodegenerative disorders. Neurol Res. 2017 Jan;39(1):65-72. doi: 10.1080/01616412.2016.1250458. Epub 2016 Oct 27. PMID: 27786097.
8. Duggan KA, Hodge G, Chen J, Hunter T. Vasoactive intestinal peptide infusion reverses existing myocardial fibrosis in the rat. Eur J Pharmacol. 2019 Nov 5;862:172629. doi: 10.1016/j.ejphar.2019.172629. Epub 2019 Aug 23. PMID: 31449808.
9. Wilkins BW, Chung LH, Tublitz NJ, Wong BJ, Minson CT. Mechanisms of vasoactive intestinal peptide-mediated vasodilation in human skin. J Appl Physiol (1985). 2004 Oct;97(4):1291-8. doi: 10.1152/japplphysiol.00366.2004. Epub 2004 May 21. PMID: 15155712.
10. Sun X, Huang Y, Zhang YL, Qiao D, Dai YC. Research advances of vasoactive intestinal peptide in the pathogenesis of ulcerative colitis by regulating interleukin-10 expression in regulatory B cells. World J Gastroenterol. 2020 Dec 28;26(48):7593-7602. doi: 10.3748/wjg.v26.i48.7593. PMID: 33505138; PMCID: PMC7789055.