VIP

Vasoactive intestinal peptide (VIP, vasoactive intestinal polypeptide, PHM27) is a short peptide hormone made in the gut, pancreas, and brain of most vertebrate animals including humans. VIP binds to class II G protein-coupled receptors and is known to

• increase the breakdown of glycogen in liver and muscle,
• lower blood pressure,
• relax smooth muscle throughout the GI tract,
• stimulate contraction of cardiac muscle (by boosting both heart rate and strength of contractions),
• stimulate the secretion of water in various areas of the GI tract,
• affect vaginal lubrication,
• regulate prolactin release,
• protect cartilage,
• protect neurons against ischemia and oxidative stress,
• affect autonomic nerve function, and
• help to synchronize the central nervous system (specifically neurons in the suprachiasmatic nucleus) with light cues for regulating circadian rhythm.

VIP has long been an interest in research for all of the reasons above and more. There is a great deal of scientific literature on this particular peptide, making it nearly impossible to cover all of the many facets of VIP research. Below is a summary of some of the high points, including the most important aspect of VIP research – the finding that it VIP can reduce inflammation and fibrosis in a number of different organs.

Amino Acid Sequence: HSDAVFTDNYXRLRKQMAVKKYLNSXLN
Molecular Formula: C₁₄₇H₂₃₇N₄₃O₄₃S
Molecular Weight:
Human Gene: VIP; 6q25.2
PubChem CID: 44567960
CAS Number: 37221-79-7
Synonyms: VIP, PHM27, Vasoactive intestinal polypeptide

Source: PubChem

Bowel Inflammation

As it turns out, one of the primary producers of VIP is the immune nerve fibers in blood vessels of the central and peripheral nervous systems and heart. Additionally, VIP is produced directly by cells of the immune system where it helps to promote Th2-type responses which can reduce inflammation and quiet the immune system. VIP and analogues derived from it have been heavily investigated as potential inflammatory mediators in intestinal disease, heart disease, and neuroinflammatory conditions[1], [2].

The various roles of VIP in immunomodulation:

Source: Pharmacological Reviews

In the setting of inflammatory bowel diseases (IBDs) like Crohn’s and ulcerative colitis, VIP has been found to improve intestinal barrier homeostasis and reduce inflammation driven by Th1 cell actions[3]. This latter approach, in particular, appears to generate T cells capable of producing the inflammation suppressing peptide interleukin-10[4]. In recent years it has become apparent that Th1 inflammation is one of several important pathways in IBD.

The benefit of improved intestinal barrier function should not be understated as it is hypothesized to be a contributing cause in the pathogenesis of inflammatory bowel disease. In particular, it is thought that compromised barrier function leads to increased antigenic material in the space between cells where it is more likely to interact with immune cells and set off an inflammatory response. Mitigating antigen presentation to immune cells via improved barrier function secondary to VIP would thus reduce what is believed to be one of the first steps in the cascade of events leading to colitis and severe inflammatory bowel disease[3].

Vasoactive Intestinal Peptide in Lung Function

There are at least two ways in which VIP impacts lung function. In the first mechanism, VIP modulates pulmonary vascular remodeling in response to inflammation. It appears to have this effect though suppression of a peptide call NFAT, which activates T cells and leads to increased inflammation[5]. Consistent with its roll in modulating inflammation in other tissues, VIP appears to control T-cell mediate inflammation in the lungs, a process that heretofore has been difficult to address in models of inflammation. In particular, NFAT suppression may play a very important role in preventing pulmonary fibrosis, the end stage of a number of inflammatory conditions such as COPD, sarcoidosis, etc[6]. Thus, VIP may provide a very useful mechanism for preventing the kind of end stage lung disease that can only be cured by transplant and which often results in serious morbidity and even death.

VIP also appears to inhibit the proliferation of smooth muscles in pulmonary tissue. Smooth muscle cell proliferation is one of the long-term consequences of lung inflammation and is a particular problem in bronchial asthma that has been uncontrolled for extended periods[7]. There is hope that VIP will provide a mechanism by which to mitigate the effects of long-term inflammation secondary to asthma.

There is also exceptional evidence that the vasodilatory effects of VIP, which are known to help control blood pressure, may have a highly potent effect in pulmonary vasculature. Preliminary research shows that VIP lowers blood pressure significantly in the pulmonary artery, leading to increased cardiac output and improved venous oxygen saturation[8]. While more work remains to be done, there is significant hope that VIP will offer a new modality for improving lung function in the setting of primary vascular conditions.

VIP in Transplants

One of the primary problems with organ transplants is rejection by the body’s immune system. No matter how good the match between donor and recipient, the body mounts a response against transplanted organs that eventually leads to their destruction and failure. Currently, the only solution to this problem is the use of broad-spectrum anti-inflammatory medications. Unfortunately, these drugs can lead to susceptibility to serious infections and have side effects of their own, such as scarring and organ fibrosis, that can limit their use.

Research on VIP has revealed that the peptide affects dendritic cells (DCs). DCs are important in the immune response because they help the body to recognize antigens and mount appropriate countermeasures. By reducing DC proliferation and activation, VIP helps to thwart immune responses before they are even mounted. Interestingly, this function seems to favor DCs attached to antigens that are tolerogenic. In other words, VIP selectively inhibits the proliferation of DCs that might cause an autoimmune reaction. This is an area of active research as VIP could potentially reduce transplant rejection with fewer infection-promoting side effects[9]. This could make VIP or an analogue of it the foundation of transplant anti-rejection medicine in the future.

VIP as a Neuroprotectant

The role of VIP in the central nervous system is threefold: neurotransmitter, neurotrophic/neurogenic, and anti-inflammatory/neuroprotectant. As with the intestine, VIP’s role in the CNS begins with maintaining barriers. In this case, the peptide helps to maintain the very critical function of the blood-brain barrier (BBB)[10]. The BBB is a layer of cellular protection between blood vessels and the tissue of the central nervous system. It regulates what enters neurological tissue and thus controls everything from nutrition and oxygenation to immune function. Compromise of the BBB has been implicated in the pathophysiology of multiple sclerosis, encephalomyelitis, and even stroke.

VIP has also been shown to regulate the accumulation of beta amyloid in mouse models of Alzheimer’s disease and is known to offer neuroprotective effects in Parkinson’s disease[11], [12]. There is also evidence that VIP is an important neuroprotectant in the developing brain where it helps to ward of excitotoxic white matter damage and improve neuron fatty acid myelination[13]. In the case of Parkinson’s disease, VIP appears to offer a similar benefit as in other inflammatory settings by shifting the immune balance away from inflammatory Th1 responses toward anti-inflammatory Th2 responses[14].

The exact role of VIP in Alzheimer’s disease (AD) is less clear. Research shows that processing of VIP is inhibited in AD with levels of the peptide as well as amino acid byproducts being lower in the brains of people affected by AD[15], [16]. Again, the research is unclear at this point, but infusion of VIP into the brains of mice shows a substantial reduction in beta amyloid levels, proving that the peptide plays an important role in the pathophysiology of the disease.

The effects of VIP in protecting the CNS appear to be mediated through VPAC1 and VPAC2 receptors. In both cases, stimulation appears to result in increased secretion of neurotrophic factors like ADNP (activity-dependent neurotrophic factor) and BDNF (brain-derived neurotrophic factor). Both of these peptides help to protect synapses and astrocytes.

Source: PubChem

Cardiac Fibrosis

As with lung disease, fibrosis is the end stage of a number of different heart conditions. Cardiac fibrosis leads to a number of serious problems including valve dysfunction, decreases in contractility, changes in cardiac filling, and electrical problems. As in lung disease, cardiac fibrosis is the common end stage of many heart conditions and generally necessitates transplant in order to avoid mortality.

To date, most cardiac research has focused on preventing scar formation from occurring. A number of commonly used drugs can, at least to some extent, help to slow the process of cardiac remodeling that leads to scarring. Unfortunately, very few cases are 100% successful and most people experience progressive fibrosis and decline in cardiac function. Recent research in rats, however, indicates that VIP may not only slow fibrosis down, but can reverse scarring. It appears that at least part of this effect is mediated through a massive reduction in angiotensinogen and angiotensin receptor type 1a expression. This makes sense as angiotensin receptor blockers and ACE inhibitors have long been known to slow down cardiac modeling/fibrosis and are in fact the first line of prevention for fibrosis[17].

Source: ScienceDirect

Vasoactive Intestinal Peptide and COVID 19

An interesting recent development out of Switzerland and the United States indicates that a synthetic version of VIP called aviptadil (RLF-100) may help to alleviate the lung complications in severe cases of Covid 19. Aviptadil, like VIP, inhibits pro-inflammatory cytokine production. In the lungs, this translates into protection of type-2 alveolar cells, the cells responsible for the bulk of oxygen exchange that takes place in the lungs. In fact, it appears that Aviptadil may actually prevent the SARS-2 coronavirus from penetrating these cells and infecting them. There are currently ongoing phase 2/3, placebo-controlled trials to investigate the effectiveness of this VIP derivative in protecting against serious complications of COVID 19[18].

According to Dr. Jonathan Javitt, CEO of NeuroRX (NeuroRX has paired with the maker of aviptadil to expedite development and use of the drug in the treatment of COVID), rapid recovery is seen in patients on ventilators and ECMO just three days after treatment with RLF-100. This is even that case in patients with severe medical comorbidities. The drugs has been administered on an emergency basis to patients too ill to be admitted to the clinical trial. Dr. Javitt points out that no antiviral agent has demonstrated the kind of rapid recovery from infection and demonstrated inhibition of viral replication the way that Aviptadil has.

Vasoactive Intestinal Peptide and COVID 19

VIP is a member of a much larger group of neuro and endocrine peptides. It has been shown to have a number of effects in relation to the central nervous system, GI tract, pulmonary tissue, and immune system. It is known to play an active role in embryonic growth and development.

Research shows that VIP can help to reduce inflammation throughout the body, but that it is particularly useful in the setting of neurodegenerative disease, pulmonary fibrosis, inflammatory bowel disease, and cardiac fibrosis. The peptide appears to be highly effective in a number of fibrotic pathways and may offer treatment benefits in the common process of fibrosis that leads to so much morbidity and mortality.

In addition to its antifibrotic effects, which appear to be mediated through anti-inflammatory actions, VIP is also a potent immune system regulator and general anti-inflammatory. The peptide has also been shown to protect the central nervous system against insult and is of active interest for its ability to preserve cognitive function in the setting of neurodegenerative disease.

Finally, synthetic versions of VIP have shown promise in treating COVID 19 and have been fast-tracked by the FDA for stage 2/3 clinical trials. This may ultimately prove beneficial for other VIP-related treatments as evidence from successful clinical trials can help to inform future clinical trials and provide pharmaceutical companies with incentive to pursue therapeutics that have an increased potential of being approved for use in humans. The next decade is likely to bring a great deal of innovation and research to vasoactive intestinal peptide.

VIP exhibits minimal side effects, low oral and excellent subcutaneous bioavailability in mice. Per kg dosage in mice does not scale to humans. VIP for sale at Peptide Sciences is limited to educational and scientific research only, not for human consumption. Only buy VIP if you are a licensed researcher.

Article Author

The above literature was researched, edited and organized by Dr. E. Logan, M.D. Dr. E. Logan holds a doctorate degree from Case Western Reserve University School of Medicine and a B.S. in molecular biology.

Scientific Journal Author

Dr. Jonathan Javitt is a physician with a background in information technology, health economics, and public health. Dr. Javitt graduated in 1978 with honors in Biochemistry from Princeton University and earned his M.D. at Cornell University Medical College. He was awarded a Kellogg Foundation Fellowship to attend the Harvard School of Public Health, from which he graduated with an M.P.H. in Health Policy and Management. In 2015, he was designated an Alumnus of Merit, the highest honor bestowed by Harvard University to graduates of the School of Public Health. His scientific publications have been cited by more than 17,000 people and he is ranked among the top 1% of quoted scientists worldwide. At the Potomac Institute, he has focused on projects related to biodefense, drug and device approval policy, and the needs of first responders. Dr. Javitt previously served as a commissioned Presidential appointee in the areas of health care and biodefense. 

Dr. Jonathan Javitt is being referenced as one of the leading scientists involved in the research and development of VIP. In no way is this doctor/scientist endorsing or advocating the purchase, sale, or use of this product for any reason. There is no affiliation or relationship, implied or otherwise, between Peptide Sciences and this doctor. The purpose of citing the doctor is to acknowledge, recognize, and credit the exhaustive research and development efforts conducted by the scientists studying this peptide. Dr. Jonathan Javitt is listed in [18] under the referenced citations.

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3. S. Seo et al., “Vasoactive intestinal peptide decreases inflammation and tight junction disruption in experimental necrotizing enterocolitis,” J. Pediatr. Surg., vol. 54, no. 12, pp. 2520–2523, Dec. 2019, doi: 10.1016/j.jpedsurg.2019.08.038.
   
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5. S. I. Said, “The vasoactive intestinal peptide gene is a key modulator of pulmonary vascular remodeling and inflammation,” Ann. N. Y. Acad. Sci., vol. 1144, pp. 148–153, Nov. 2008, doi: 10.1196/annals.1418.014.
   
6. A. M. Szema et al., “NFATc3 and VIP in Idiopathic Pulmonary Fibrosis and Chronic Obstructive Pulmonary Disease,” PloS One, vol. 12, no. 1, p. e0170606, 2017, doi: 10.1371/journal.pone.0170606.
   
7. “Vasoactive Intestinal Peptide – an overview | ScienceDirect Topics.” https://www.sciencedirect.com/topics/neuroscience/vasoactive-intestinal-peptide (accessed Jan. 01, 2021).
   
8. V. Petkov et al., “Vasoactive intestinal peptide as a new drug for treatment of primary pulmonary hypertension,” J. Clin. Invest., vol. 111, no. 9, pp. 1339–1346, May 2003, doi: 10.1172/JCI17500.
   
9. A. Chorny, E. Gonzalez-Rey, and M. Delgado, “Regulation of dendritic cell differentiation by vasoactive intestinal peptide: therapeutic applications on autoimmunity and transplantation,” Ann. N. Y. Acad. Sci., vol. 1088, pp. 187–194, Nov. 2006, doi: 10.1196/annals.1366.004.
   
10. D. R. Staines, E. W. Brenu, and S. Marshall-Gradisnik, “Postulated vasoactive neuropeptide immunopathology affecting the blood–brain/blood–spinal barrier in certain neuropsychiatric fatigue-related conditions: A role for phosphodiesterase inhibitors in treatment?,” Neuropsychiatr. Dis. Treat., vol. 5, pp. 81–89, 2009, Accessed: Jan. 01, 2021. [Online]. Available: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2695238/.
    
11. F. R. O. de Souza, F. M. Ribeiro, and P. M. d’ Almeida Lima, “Implications of VIP and PACAP in Parkinson’s disease: what do we know so far?,” Curr. Med. Chem., Mar. 2020, doi: 10.2174/0929867327666200320162436.
    
12. O. T. Korkmaz et al., “Vasoactive Intestinal Peptide Decreases β-Amyloid Accumulation and Prevents Brain Atrophy in the 5xFAD Mouse Model of Alzheimer’s Disease,” J. Mol. Neurosci. MN, vol. 68, no. 3, pp. 389–396, Jul. 2019, doi: 10.1007/s12031-018-1226-8.
    
13. P. Gressens, L. Besse, P. Robberecht, I. Gozes, M. Fridkin, and P. Evrard, “Neuroprotection of the developing brain by systemic administration of vasoactive intestinal peptide derivatives,” J. Pharmacol. Exp. Ther., vol. 288, no. 3, pp. 1207–1213, Mar. 1999.
    
14. R. L. Mosley et al., “A Synthetic Agonist to Vasoactive Intestinal Peptide Receptor-2 Induces Regulatory T Cell Neuroprotective Activities in Models of Parkinson’s Disease,” Front. Cell. Neurosci., vol. 13, p. 421, 2019, doi: 10.3389/fncel.2019.00421.
    
15. M. Yasuda, K. Maeda, T. Kakigi, N. Minamitani, T. Kawaguchi, and C. Tanaka, “Low cerebrospinal fluid concentrations of peptide histidine valine and somatostatin-28 in Alzheimer’s disease: altered processing of prepro-vasoactive intestinal peptide and prepro-somatostatin,” Neuropeptides, vol. 29, no. 6, pp. 325–330, Dec. 1995, doi: 10.1016/0143-4179(95)90003-9.
    
16. R. H. Perry, G. J. Dockray, R. Dimaline, E. K. Perry, G. Blessed, and B. E. Tomlinson, “Neuropeptides in Alzheimer’s disease, depression and schizophrenia. A post mortem analysis of vasoactive intestinal peptide and cholecystokinin in cerebral cortex,” J. Neurol. Sci., vol. 51, no. 3, pp. 465–472, Sep. 1981, doi: 10.1016/0022-510x(81)90123-4.
    
17. K. A. Duggan, G. Hodge, J. Chen, and T. Hunter, “Vasoactive intestinal peptide infusion reverses existing myocardial fibrosis in the rat,” Eur. J. Pharmacol., vol. 862, p. 172629, Nov. 2019, doi: 10.1016/j.ejphar.2019.172629.
    
18. C. Smith, BGR, Aug. 03, 2020. https://bgr.com/2020/08/03/coronavirus-cure-rlf-100-aviptadil-phase-3-trial/ (accessed Jan. 01, 2021).

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