Vascular Endothelial Growth factor-C Stimulates the Lymphatic Pump by a VEGF receptor-3-dependent Mechanism

Am J Physiol Heart Circ Physiol. 2007 Jul;293(1):H709-18. doi: 10.1152/ajpheart.00102.2007. Epub 2007 Mar 30.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Dose-Response Relationship, Drug
  • Lymphatic Vessels / drug effects
  • Lymphatic Vessels / physiology*
  • Male
  • Mesentery / drug effects
  • Mesentery / physiology*
  • Rats
  • Rats, Sprague-Dawley
  • Vascular Endothelial Growth Factor C / administration & dosage*
  • Vascular Endothelial Growth Factor Receptor-3 / metabolism*

Substances

  • Vascular Endothelial Growth Factor C
  • Vascular Endothelial Growth Factor Receptor-3