Compounds / VIP
Immune VIPPHM-27

VIP

A 28-amino-acid neuropeptide with vasodilatory, immunomodulatory, and thermoregulatory properties — studied in inflammatory conditions and, more recently, menopausal vasomotor symptoms.

Overview

Vasoactive Intestinal Peptide (VIP) is a 28-amino-acid neuropeptide widely distributed in the central and peripheral nervous systems, gastrointestinal tract, and immune tissues. It was first isolated from porcine small intestine in 1970 and named for its potent vasodilatory effects. VIP acts through VPAC1 and VPAC2 receptors, with downstream effects on smooth muscle relaxation, immune cell modulation, circadian rhythm regulation, and thermoregulation. VIP is one of the primary neurotransmitters in the suprachiasmatic nucleus (SCN), the brain's master circadian clock. It is also expressed in the hypothalamic regions that regulate core body temperature — making it a mechanistically relevant research target for the thermoregulatory dysregulation that underlies hot flashes and night sweats in menopause.

Mechanism

VIP binds to VPAC1 and VPAC2 receptors (both Gs-coupled GPCRs), activating adenylate cyclase and elevating cAMP. Key downstream effects include: smooth muscle relaxation and vasodilation (peripheral blood flow), inhibition of pro-inflammatory cytokine release (TNF-α, IL-6, IL-12), promotion of anti-inflammatory Treg differentiation, and neurotransmitter modulation in the hypothalamus and SCN. In thermoregulation, VIP neurons in the SCN communicate with hypothalamic temperature-regulating circuits; alterations in VIP signaling have been linked to impaired thermoregulatory set-point control — the proposed mechanism for hot flashes in estrogen withdrawal states.

Research Areas

Menopausal vasomotor symptoms (hot flashes, night sweats)Inflammatory bowel disease and gut motilityPulmonary arterial hypertensionAutoimmune disease modulation (rheumatoid arthritis, Crohn's)Circadian rhythm and sleep regulationNeuroprotection

Side Effects (Preclinical)

  • – Facial flushing (vasodilatory effect)
  • – Hypotension at higher doses
  • – Nausea
  • – Transient tachycardia

Cautions

  • – Short plasma half-life makes systemic delivery challenging
  • – Aviptadil (synthetic VIP) is under FDA review for ARDS — not yet approved
  • – Most human data comes from IV infusion or inhaled routes; SQ research is early-stage

Menopause & Women's Health Relevance

VIP neurons sit at the intersection of thermoregulation and the circadian clock — the two systems most disrupted by menopause. Research suggests that estrogen normally upregulates VIP expression in hypothalamic thermoregulatory circuits; estrogen withdrawal reduces VIP signaling, narrowing the thermoneutral zone and making women hypersensitive to small temperature changes (the proposed mechanism for hot flashes). VIP is also anti-inflammatory — relevant given that the inflammatory tone increases measurably at menopause.

hot flashesnight sweatsinflammationsleep disruptionvasomotor symptoms
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What the research shows

VIP’s role in thermoregulation is primarily studied at the hypothalamic level, where VIP neurons in the SCN project to preoptic thermoregulatory areas. The narrowed thermoneutral zone in post-menopausal women — where the body triggers sweating or shivering in response to temperature shifts that pre-menopausal women tolerate easily — is consistent with impaired VIP/thermoregulatory signaling.

The anti-inflammatory profile has attracted broader interest: VIP inhibits NF-κB-driven inflammatory cascades and promotes regulatory T cell differentiation. This is relevant to menopause given that estrogen withdrawal is associated with a measurable shift toward a pro-inflammatory state, contributing to joint pain, cardiovascular risk, and cognitive changes.

Clinical context: Aviptadil (RLF-100), a synthetic VIP formulation, has been studied in Phase II/III trials for pulmonary arterial hypertension and ARDS, providing human safety data — though menopause-specific trials do not yet exist.

References

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