Urotensin II induces phenotypic differentiation, migration, and collagen synthesis of adventitial fibroblasts from rat aorta

J Hypertens. 2008 Jun;26(6):1119-26. doi: 10.1097/HJH.0b013e3282fa1412.

Abstract

Background: Urotensin II is a new potent vasoconstrictor. Nevertheless, little is known about its effects on the activation of adventitial fibroblasts.

Objective: To explore the effects of urotensin II on phenotypic differentiation, migration, and collagen I synthesis of rat aortic adventitial fibroblasts.

Methods: Growth-arrested adventitial fibroblasts were incubated in serum-free medium with urotensin II and some inhibitors of signal transduction pathways. The alpha-smooth muscle-actin expression, collagen I synthesis and migration of adventitial fibroblasts induced by urotensin II were evaluated by western blot, enzyme-linked immunosorbant assay, and the transwell technique, respectively.

Results: Urotensin II induced the [alpha]-smooth muscle-actin expression in a dose-dependent and time-dependent manner, with maximal effect at a concentration of 10(-8) mol/l at 24 h (79.9%); it also caused a dose-dependent increase in collagen I synthesis, with maximal effect at a concentration of 10(-7) mol/l (42.6%). The Ca2+ channel blocker nicardipine (10(-5) mol/l), protein kinase C inhibitor H7 (10(-5) mol/l), Rho protein kinase inhibitor Y-27632 (10(-5) mol/l), calcineurin inhibitor cyclosporine A (10(-5) mol/l), and mitogen-activated protein kinase inhibitor PD98059 (10(-5) mol/l) inhibited urotensin II-induced increases in [alpha]-smooth muscle-actin expression and collagen synthesis. Meanwhile, urotensin II stimulated the migration of adventitial fibroblasts dose dependently, with maximal effect at a concentration of 10(-8) mol/l, which was 5.7-fold greater than that of the control. This effect could also be inhibited by PD98059, H7, cyclosporine A, and Y-27632 but not nicardipine.

Conclusion: Urotensin II may stimulate adventitial fibroblasts phenotypic conversion, migration, and collagen I synthesis through the protein kinase C, mitogen-activated protein kinase, calcineurin, Rho kinase, and/or Ca2+ signal transduction pathways, contributing to the development of vascular remodeling through adventitial fibroblasts activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta / cytology
  • Calcineurin / metabolism
  • Calcium Signaling / physiology
  • Cell Differentiation / physiology*
  • Cell Movement / physiology*
  • Cells, Cultured
  • Collagen Type I / biosynthesis*
  • Fibroblasts / metabolism
  • Fibroblasts / physiology*
  • MAP Kinase Signaling System / physiology
  • Male
  • Mitogen-Activated Protein Kinases / metabolism
  • Phenotype
  • Protein Kinase C / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Urotensins / physiology*
  • Vascular Diseases / physiopathology
  • rho-Associated Kinases / metabolism

Substances

  • Collagen Type I
  • Urotensins
  • urotensin II
  • rho-Associated Kinases
  • Protein Kinase C
  • Mitogen-Activated Protein Kinases
  • Calcineurin