VIP (Vasoactive Intestinal Peptide) Research: What Published Studies Have Investigated

What is VIP?

What is VIP? Vasoactive intestinal peptide is an endogenous 28-residue peptide, sequence HSDAVFTDNYTRLRKQMAVKKYLNSILN. UniProt entry P01282 records it as residues 125–152 of a larger precursor protein, and records the final asparagine as being C-terminally amidated — a post-translational modification that the sequence letters alone do not record, and one that matters for receptor binding across this peptide family.

The same precursor yields a second peptide, PHM-27, from residues 81–107, itself amidated at a C-terminal methionine. One gene, two secreted peptides, is a common arrangement in neuropeptide biology and it has a practical consequence for this literature: several early studies and several knockout models affect both products, which is why some of the mouse work below is described as VIP- and PHI-deficient rather than VIP-deficient alone.

VIP belongs to the secretin/glucagon superfamily of peptides, which is the structural context for its receptors being class B G-protein-coupled receptors. Its close relative in that family, PACAP, shares two of the three receptors — a fact that shapes every mechanistic question asked about VIP.

Discovery and origin in the literature

Isolated as a vasodilator, named for it

Said and Mutt reported the isolation in Science in 1970 (PMID 5450698) under the title “Polypeptide with broad biological activity: isolation from small intestine.” The material came from porcine small intestine, and the name records the first property observed: a vasoactive substance of intestinal origin. That naming convention — describing what a molecule did in the assay that found it — is why the name says nothing about the circadian and immunological work that dominates the modern literature.

Sequence, then synthesis

The structure followed four years later. Mutt and Said reported the amino-acid sequence of the porcine vasoactive intestinal octacosapeptide in the European Journal of Biochemistry in 1974 (PMID 4829446), using kallikrein in its determination. In the same year Bodanszky, Klausner and Said published a total synthesis of the peptide in the Journal of the American Chemical Society (PMID 4854585). Sequence and synthesis in the same year is what turned VIP from an extract into a reagent, and it is the reason the pharmacology literature below could develop at all.

Reference data

The molecule facts below are drawn from the public record (UniProt P01282 and PubChem CID 53314964). They describe identity and physical form only.

The amidation row is the one to read twice. The PubChem formula and mass above correspond to that database’s catalogued entry; the endogenous peptide as annotated in UniProt carries a C-terminal amide, which changes the expected mass by approximately one dalton relative to the free acid. On a 3327 Da molecule that is a small difference and a real one, and it is exactly what a mass spectrum is for. No reconstitution procedure, quantity or route is given or implied on this page.

Mechanisms researchers have examined

The VIP mechanism literature is organised around receptor pharmacology more rigorously than most peptides in this catalogue, because the receptors were cloned, named and assigned by a formal nomenclature committee. Each point below is what studies characterise:

• Three receptors, two ligands — Harmar and colleagues (2012, Br J Pharmacol, PMID 22289055) set out the IUPHAR account: VPAC1 and VPAC2 bind VIP and PACAP with comparable affinity, while PAC1 is PACAP-preferring. Any experiment attributing an effect to “VIP signalling” without specifying which receptor subtype, and without accounting for PACAP, is under-specified, and the review says so.
• Class B GPCR signalling — these are Gs-coupled receptors, and adenylate cyclase activation with cAMP accumulation is the canonical readout in the pharmacology literature. Much of the receptor-characterisation work uses cAMP as its measured output.
• Synchrony among circadian clock neurons — Aton and colleagues (2005, Nat Neurosci, PMID 15750589) reported that VIP mediates circadian rhythmicity and synchrony in mammalian clock neurons. The mechanistic claim here is unusually specific: not that the peptide drives a rhythm, but that it keeps a population of oscillating cells in phase with one another.
• Immune-cell modulation — Delgado, Pozo and Ganea (2004, Pharmacol Rev, PMID 15169929) reviewed VIP in immunomodulation across macrophage, dendritic-cell and T-cell systems, describing effects on inflammatory mediator production and on T-helper differentiation in the models examined.
• Smooth-muscle relaxation and secretion — the original gastrointestinal and vascular pharmacology, and the property the molecule is named for.

Each bullet names a mechanism examined in a defined system, not an effect in a reader.

Research areas in the literature

Circadian neuroscience

This is arguably where VIP has been most productive as a research tool. Colwell and colleagues (2003, Am J Physiol, PMID 12855416) reported disrupted circadian rhythms in mice deficient in VIP and PHI — the two products of the same precursor. Aton and colleagues (2005) then characterised the cellular basis in suprachiasmatic-nucleus neurons. Together these established VIP as a coupling signal within the master circadian pacemaker, and that role is now standard textbook material in chronobiology.

Immunology

The Delgado and Ganea programme built a large body of work on VIP as an endogenous anti-inflammatory mediator in cellular and rodent models, summarised in the 2004 Pharmacological Reviews article. It is a review of preclinical immunology, and the distance between “modulates dendritic-cell phenotype in culture” and any clinical statement is the whole distance this page is careful about.

Gastroenterology and vascular physiology

The founding literature, and the reason VIP appears in clinical medicine at all — chiefly as the hormone measured in the diagnosis of VIPoma, a rare secreting tumour. That is a diagnostic role for an endogenous measurement, not an interventional one.

The aviptadil trials

Synthetic VIP under the name aviptadil was tested in COVID-19-associated respiratory failure, and this is the only place where administered VIP meets randomised human evidence. Youssef and colleagues (2022, Crit Care Med, PMID 36044317) reported a multicentre placebo-controlled trial in 196 patients whose primary endpoint did not reach statistical significance (odds ratio 1.6, 95% CI 0.86–3.11); the authors reported secondary and subgroup findings they considered favourable and argued for a positive benefit-risk assessment. The larger TESICO trial (Brown and colleagues, 2023, Lancet Respir Med, PMID 37348524) enrolled 473 participants across 28 US sites; its independent data and safety monitoring board recommended stopping the aviptadil arm for futility, and the reported odds ratio for a better category of the primary outcome at day 90 was 1.11 (95% CI 0.80–1.55, p = 0.54).

Research models and evidence status

VIP is genuinely well characterised as a molecule and as a receptor ligand. That is a different statement from any claim about what it does in a person.

What is solidly established

The sequence, the precursor and its second product, the amidation, the synthesis route, the three-receptor pharmacology with its formal nomenclature, and the role of endogenous VIP as a coupling signal in the suprachiasmatic nucleus. This is textbook-grade material with fifty years of independent replication behind it, which is why the reference table above can be filled out completely — an unusual luxury in this catalogue.

What is not established

Any therapeutic effect of administered VIP. The two randomised, placebo-controlled trials on the record both failed their primary endpoints, and the larger of the two was halted for futility by an independent monitoring board. The immunological literature is preclinical. The circadian literature concerns the endogenous peptide’s role in an intact system, not the effect of adding more of it. There is no established receptor-subtype selectivity for VIP itself — it engages VPAC1 and VPAC2 comparably, which limits how precisely any observed effect can be attributed. And the peptide’s short circulating half-life is a standing obstacle that the drug-development literature has repeatedly noted.

Nothing in this literature establishes any property of the supplied research material in a person. This page makes no efficacy, therapeutic, anti-inflammatory, respiratory, circadian or other use claim of any kind, and the material is supplied for laboratory research use only — not for human or veterinary use.

How to verify this compound yourself

At 28 residues with a post-translational modification and a methionine in the chain, VIP puts several specific demands on its certificate of analysis:

• Mass-spec identity, and the amide question — the endogenous peptide is C-terminally amidated. Amidated and free-acid forms differ by approximately one dalton, which a competent mass spectrometer resolves easily on a ≈ 3327 Da molecule but which no HPLC purity percentage will ever record. Where the distinction matters for an experiment, the mass spectrum is where it is settled.
• HPLC purity — 28 residues is a long enough synthesis that deletion sequences are a real component of the crude product. The purity figure summarises how cleanly full-length material separates from them.
• Methionine oxidation — the single methionine at position 17 can oxidise to the sulfoxide, adding 16 Da and often producing a distinguishable earlier-eluting peak. This is a common, well-documented degradation route for methionine-containing peptides and it is visible on both the trace and the spectrum.
• Counter-ion and net peptide content — a basic sequence with multiple lysines and arginines is normally isolated as a salt, commonly trifluoroacetate. A documentation question, but one that changes how much peptide a given mass actually contains.
• Endotoxin — essential for a compound whose principal preclinical literature is immunological, since endotoxin drives exactly the inflammatory readouts these assays measure. Reported in EU/mL where tested, independent of chemical purity.

See how to read a COA for what each certificate line means, and how to verify peptide purity for how the methods fit together. The exact batch received can be checked on the self-serve verify tool.

Research-grade sourcing and verification

VIP is not held in stock. It is listed on our sourcing catalogue as available to order — our supplier lists it, we have not bought it, and material of this kind typically takes about two to three weeks to reach us. For laboratory research use only, it is supplied with a per-batch Certificate of Analysis reporting HPLC purity (%) and mass-spec identity confirmation, verifiable at the lot level. For a neighbouring hypothalamic peptide with an equally formal receptor pharmacology, see gonadorelin research; for another endogenous neuropeptide documented here with tight compliance framing, see oxytocin research. This is sourcing and quality-assurance framing only.

Frequently asked questions

Literature cited

1. Said SI, Mutt V. “Polypeptide with broad biological activity: isolation from small intestine.” Science. 1970;169(3951):1217–1218. PMID 5450698. pubmed.ncbi.nlm.nih.gov/5450698.
2. Mutt V, Said SI. “Structure of the porcine vasoactive intestinal octacosapeptide. The amino-acid sequence. Use of kallikrein in its determination.” Eur J Biochem. 1974;42(2):581–589. PMID 4829446. pubmed.ncbi.nlm.nih.gov/4829446.
3. Bodanszky M, Klausner YS, Said SI. “Synthesis of the vasoactive intestinal peptide (VIP).” J Am Chem Soc. 1974. PMID 4854585. pubmed.ncbi.nlm.nih.gov/4854585.
4. Colwell CS, Michel S, Itri J, et al. “Disrupted circadian rhythms in VIP- and PHI-deficient mice.” Am J Physiol Regul Integr Comp Physiol. 2003;285(5):R939–R949. PMID 12855416. pubmed.ncbi.nlm.nih.gov/12855416.
5. Delgado M, Pozo D, Ganea D. “The significance of vasoactive intestinal peptide in immunomodulation.” Pharmacol Rev. 2004;56(2):249–290. PMID 15169929. pubmed.ncbi.nlm.nih.gov/15169929.
6. Aton SJ, Colwell CS, Harmar AJ, Waschek J, Herzog ED. “Vasoactive intestinal polypeptide mediates circadian rhythmicity and synchrony in mammalian clock neurons.” Nat Neurosci. 2005;8(4):476–483. PMID 15750589. pubmed.ncbi.nlm.nih.gov/15750589.
7. Harmar AJ, Fahrenkrug J, Gozes I, et al. “Pharmacology and functions of receptors for vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide: IUPHAR review 1.” Br J Pharmacol. 2012;166(1):4–17. PMID 22289055. pubmed.ncbi.nlm.nih.gov/22289055.
8. Youssef JG, Lavin P, Schoenfeld DA, et al. “The Use of IV Vasoactive Intestinal Peptide (Aviptadil) in Patients With Critical COVID-19 Respiratory Failure: Results of a 60-Day Randomized Controlled Trial.” Crit Care Med. 2022;50(11):1545–1554. PMID 36044317. pubmed.ncbi.nlm.nih.gov/36044317. Primary endpoint not statistically significant.
9. Brown SM, Barkauskas CE, Grund B, et al. “Intravenous aviptadil and remdesivir for treatment of COVID-19-associated hypoxaemic respiratory failure in the USA (TESICO): a randomised, placebo-controlled trial.” Lancet Respir Med. 2023;11(9):791–803. PMID 37348524. pubmed.ncbi.nlm.nih.gov/37348524. Aviptadil arm stopped for futility.
10. UniProt Consortium. “P01282 (VIP_HUMAN), VIP peptides.” uniprot.org/uniprotkb/P01282 (precursor boundaries, C-terminal amidation, PHM-27).
11. National Center for Biotechnology Information. “PubChem Compound Summary for CID 53314964, Vasoactive intestinal peptide.” pubchem.ncbi.nlm.nih.gov/compound/53314964 (formula, mass, CAS 37221-79-7).