VIP

Vasoactive Intestinal Peptide (VIP) is a 28-amino acid neuropeptide widely distributed in the central and peripheral nervous systems, gastrointestinal tract, and immune system. First isolated from porcine intestine by Said and Mutt in 1970, VIP functions as a neurotransmitter, neuromodulator, and immunomodulator with potent vasodilatory, anti-inflammatory, and neuroprotective properties. VIP acts through two receptors: VPAC1 (widely distributed) and VPAC2 (more restricted to CNS and immune cells), both Gs-coupled GPCRs that increase cAMP. Clinical investigations have explored VIP for pulmonary arterial hypertension, sarcoidosis, COPD, and autoimmune diseases, with a VIP analog (aviptadil) receiving attention during COVID-19 for acute respiratory distress syndrome.

VIP binds VPAC1 and VPAC2 receptors, activating cAMP/PKA signaling. In vascular smooth muscle, this produces vasodilation. In immune cells, cAMP elevation suppresses NF-κB-mediated inflammatory gene transcription, inhibits Th1/Th17 differentiation while promoting Treg cells, and reduces pro-inflammatory cytokines (TNF-α, IL-6, IL-12). In neurons, VIP provides neuroprotection through BDNF upregulation and anti-apoptotic signaling.

Pulmonary Hypertension Inhaled VIP reduces pulmonary artery pressure and improves right heart function. Clinical trials have been conducted. COVID-19 ARDS Aviptadil (synthetic VIP) received emergency use investigation for COVID-19-related ARDS, showing improved oxygenation. Autoimmune Diseases Preclinical efficacy in rheumatoid arthritis, multiple sclerosis, type 1 diabetes, and inflammatory bowel disease models. Neuroprotection VIP protects against excitotoxicity and promotes neural stem cell differentiation.

VPAC1/2→Gs→cAMP→PKA for vasodilation and immunomodulation. PKA→CREB for gene transcription. NF-κB suppression for anti-inflammation. BDNF/TrkB for neuroprotection.

Transient hypotension and tachycardia (vasodilation). Diarrhea (stimulates intestinal secretion). Flushing and warmth. Hypoglycemia risk at high doses. Limited human safety data for chronic systemic use.

VIP is extremely sensitive to degradation in serum (half-life <1 minute). Store lyophilized at -20°C. Reconstituted solutions must be used quickly. Inhaled and intranasal delivery bypass systemic degradation. Lipidated and PEGylated analogs under development for extended half-life.

VIP is not FDA-approved as a standalone drug. Aviptadil (synthetic VIP) has been investigated under EUA and IND for COVID-19 ARDS. Investigational for other indications. Not WADA-prohibited.