title: Vascular endothelial growth factor-C stimulates the lymphatic pump by a VEGF receptor-3-dependent mechanism.
abstract: Vascular endothelial growth factor (VEGF)-C plays an important role in lymphangiogenesis; however, functional responses of lymphatic vessels to VEGF-C have not been characterized. We tested the hypothesis that VEGF-C-induced activation of VEGF receptor (VEGFR)-3 increases lymphatic pump output. We examined the in vivo pump activity of rat mesenteric collecting lymphatics using intravital microscopy during basal conditions and during treatment with 1 nM recombinant VEGF-C, the selective VEGFR-3 agonist VEGF-Cys(156)Ser mutation (C156S; 1 nM), or 0.1 nM VEGF-A. Their specific responses were also analyzed during selective inhibition of VEGFR-3 with MAZ-51. Contraction frequency, end-diastolic diameter, end-systolic diameter, stroke volume index, pump flow index, and ejection fraction were evaluated. We also assessed arteriolar diameter and microvascular extravasation of FITC-albumin. The results show that both VEGF-C and VEGF-C156S significantly increased contraction frequency, end-diastolic diameter, stroke volume index, and pump flow index in a time-dependent manner. VEGF-A caused a different response characterized by a significantly increased stroke volume after 30 min of treatment. MAZ-51 (5 muM) caused tonic constriction and decreased contraction frequency. In addition, 0.5 and 5 muM MAZ-51 attenuated VEGF-C- and VEGF-C156S-induced lymphatic pump activation. VEGF-A caused vasodilation of arterioles, whereas VEGF-C and VEGF-C156S did not significantly alter arteriolar diameter. Also, VEGF-A and VEGF-C caused increased microvascular permeability, whereas VEGF-C156S did not. Our results demonstrate that VEGF-C increases lymphatic pumping through VEGFR-3. Furthermore, changes in microvascular hemodynamics are not required for VEGFR-3-mediated changes in lymphatic pump activity.
authors.affiliation: Department of Surgery, Division of Research, School of Medicine, University of California-Davis, 2805 50th Street, Sacramento, CA 95817, USA. jwbreslin@ucdavis.edu
authors.forename: Jerome W
authors.initials: JW
authors.lastname: Breslin
authors.forename: Nathalie
authors.initials: N
authors.lastname: Gaudreault
authors.forename: Katherine D
authors.initials: KD
authors.lastname: Watson
authors.forename: Rashell
authors.initials: R
authors.lastname: Reynoso
authors.forename: Sarah Y
authors.initials: SY
authors.lastname: Yuan
authors.forename: Mack H
authors.initials: MH
authors.lastname: Wu
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D042601:Lymphatic Vessels / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008643:Mesentery / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D042582:Vascular Endothelial Growth Factor C / Q000008:administration & dosage*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism*
chemical_list: D042582:Vascular Endothelial Growth Factor C; D040321:Vascular Endothelial Growth Factor Receptor-3