VIP research examines VPAC receptor pharmacology, cyclic-AMP signalling, smooth-muscle responses, vascular biology, gastrointestinal secretion and motility, neuropeptide signalling and immune regulation. In a mouse model of induced colitis, VIP reduced both the clinical and tissue-level severity of intestinal inflammation while lowering inflammatory cytokines including TNF-alpha, IL-1 and IL-6 (Learn more). Because VPAC receptors occur across multiple tissues, VIP is particularly useful for studying how the same peptide signal produces different responses depending on cell type and receptor expression, alongside related neuro and signalling-research peptides such as Selank and DSIP.
Said and Mutt: a hog-gut peptide with whole-body reach
VIP entered the literature in September 1970, when Sami Said and Viktor Mutt reported in Science that they had purified a 28-residue polypeptide from hog small intestine. Their extract behaved like nothing they had catalogued before. It widened systemic blood vessels, lowered blood pressure, raised cardiac output, stimulated breathing and nudged blood glucose upwards, yet it was chemically distinct from the kinins, substance P, glucagon and secretin (Learn more).
Vascular action plus intestinal origin gave the peptide its name, which has aged oddly: later mapping found VIP in nerve fibres throughout the brain, airways, gut wall and lymphoid tissue, so it is now classed primarily as a neuropeptide, and a member of the secretin–glucagon family. Mammalian VIP turned out to be strikingly conserved, with the human, pig and rat forms sharing one identical sequence, which makes rodent findings straightforward to line up against human tissue work.
VPAC1, VPAC2 and the PACAP connection
VIP acts through class B G-protein-coupled receptors, the same broad family used by secretin and glucagon. Its two main receptors, VPAC1 and VPAC2, couple to Gs, so receptor activation typically raises intracellular cyclic AMP, which is why cAMP accumulation and reporter assays are standard readouts in VIP pharmacology.
A complication makes this field interesting. A second neuropeptide, PACAP, binds both VPAC receptors with roughly the same nanomolar affinity as VIP, and the first 28 residues of PACAP-38 are around 68% identical to VIP. A third receptor, PAC1, separates the two: it binds PACAP tightly but VIP several hundred times more weakly. Researchers therefore compare VIP and PACAP side by side, with receptor-selective analogues or knockout tissue, to work out which receptor carries a given response in lung, gut, smooth muscle, immune cells or brain.
Keeping time in the suprachiasmatic nucleus
The suprachiasmatic nucleus (SCN) of the hypothalamus is the brain’s master clock, and VIP-expressing neurons are one of its defining cell populations. Two mouse studies made VIP central to circadian biology. In 2002, Harmar and colleagues in Edinburgh reported in Cell that mice lacking the VPAC2 receptor could not sustain normal rest–activity rhythms, and that the core clock genes Per1, Per2 and Cry1 lost their daily expression pattern in the SCN. Light pulses at night also failed to switch on Per1 and Per2 as they normally would.
A year later, Colwell and colleagues described mice lacking both VIP and its sister peptide PHI. Under a normal light–dark cycle they looked largely ordinary, but once moved into constant darkness their activity began about eight hours earlier than expected, their free-running period shortened, and around a quarter eventually became arrhythmic. Together these results support the view that VIP helps the thousands of individual SCN cell clocks stay synchronised with one another and with the light cycle, and SCN slice recordings remain a key model for studying it.
Immune balance: arthritis models and regulatory T cells
VIP is released by nerve fibres in lymphoid organs and is also made by some immune cells, which has made it a classic subject in neuroimmunology. The colitis study above is one of a series from Mario Delgado, Rosa Gomariz and colleagues in Madrid. In 2001 the group reported in Nature Medicine that VIP given to mice with collagen-induced arthritis reduced both how often and how severely the disease developed, with joint swelling and cartilage and bone destruction abolished in treated animals. The authors linked this to suppression of both the inflammatory and the autoimmune arms of the model.
Later work shifted attention to regulatory T cells. In culture, VIP was shown to convert naive CD4+CD25− T cells into CD4+CD25+FoxP3+ regulatory T cells, the population that restrains effector responses. That offers a mechanistic handle on why one neuropeptide quietens several unrelated inflammatory models, and why VIP features in dendritic-cell, macrophage and T-cell differentiation studies.
Lung research and the aviptadil clinical record
Sami Said spent much of his career on VIP in the lung, where it relaxes airway and pulmonary vascular smooth muscle. In 2007 his group reported that male mice lacking the VIP gene developed moderate pulmonary arterial hypertension, with right-ventricular enlargement and thickened, muscularised pulmonary arteries, and that four weeks of VIP replacement attenuated both forms of remodelling. In a small open-label phase II study, 20 people with active sarcoidosis inhaled nebulised VIP for four weeks; cells recovered by bronchoalveolar lavage produced less TNF-alpha and regulatory T-cell numbers rose.
Synthetic VIP carries the international non-proprietary name aviptadil. In the UK, aviptadil is licensed only in combination with phentolamine, as Invicorp, a prescription medicine for erectile dysfunction. During the COVID-19 pandemic, intravenous aviptadil (developed by NRx as Zyesami) was tested in critically ill patients: the company’s 196-patient trial missed its primary endpoint, the FDA twice declined emergency use authorisation, and the NIH-sponsored TESICO trial found no significant improvement in outcomes to day 90 versus placebo. Crown Peptides VIP is research material and is not any of these medicinal products.
