title: Mechanisms of VIP-induced inhibition of the lymphatic vessel pump.
abstract: Lymphatic vessels serve as a route by which interstitial fluid, protein and other macromolecules are returned to the blood circulation and immune cells and antigens gain access to lymph nodes. Lymph flow is an active process promoted by rhythmical contraction-relaxation events occurring in the collecting lymphatic vessels. This lymphatic pumping is an intrinsic property of the lymphatic muscles in the vessel wall and consequent to action potentials. Compromised lymphatic pumping may affect lymph and immune cell transport, an action which could be particularly detrimental during inflammation. Importantly, many inflammatory mediators alter lymphatic pumping. Vasoactive intestinal peptide (VIP) is a neuro- and immuno-modulator thought to be released by nerve terminals and immune cells in close proximity to lymphatic vessels. We demonstrated the presence of the peptide in lymphatic vessels and in the lymph and examined the effects of VIP on mesenteric collecting lymphatic vessels of the guinea pig using pharmacological bioassays, intracellular microelectrode electrophysiology, immunofluorescence and quantitative real-time PCR. We showed that VIP alters lymphatic pumping by decreasing the frequency of lymphatic contractions and hyperpolarizing the lymphatic muscle membrane potential in a concentration-dependent manner. Our data further suggest that these effects are mainly mediated by stimulation of the VIP receptor VPAC2 located on the lymphatic muscle and the downstream involvement of protein kinase A (PKA) and ATP-sensitive K⁺ (KATP) channels. Inhibition of lymphatic pumping by VIP may compromise lymph drainage, oedema resolution and immune cell trafficking to the draining lymph nodes.
authors.affiliation: Inflammation Research Network and Smooth Muscle Research Group, Snyder Institute of Infection, Immunity and Inflammation, Department of Physiology & Pharmacology, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada. vonderwe@ucalgary.ca
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: von der Weid
authors.forename: Sonia
authors.initials: S
authors.lastname: Rehal
authors.forename: Peter
authors.initials: P
authors.lastname: Dyrda
authors.forename: Stewart
authors.initials: S
authors.lastname: Lee
authors.forename: Ryan
authors.initials: R
authors.lastname: Mathias
authors.forename: Mozibur
authors.initials: M
authors.lastname: Rahman
authors.forename: Simon
authors.initials: S
authors.lastname: Roizes
authors.forename: Mohammad S
authors.initials: MS
authors.lastname: Imtiaz
mesh_terms: D000818:Animals; D006168:Guinea Pigs; D066298:In Vitro Techniques; D042601:Lymphatic Vessels / Q000502:physiology*; D008564:Membrane Potentials; D014660:Vasoactive Intestinal Peptide / Q000502:physiology*
chemical_list: D014660:Vasoactive Intestinal Peptide