Down-modulation of monocyte transendothelial migration and endothelial adhesion molecule expression by fibroblast growth factor: reversal by the anti-angiogenic agent SU6668

Am J Pathol. 2002 Jun;160(6):2219-30. doi: 10.1016/S0002-9440(10)61169-8.

Abstract

Basic and acidic fibroblast growth factor (bFGF and aFGF, respectively) and vascular endothelial growth factor (VEGF) exert angiogenic actions and have a role in wound healing, inflammation, and tumor growth. Monocytes and endothelial cells are involved in these processes, but the effect of FGF and VEGF on monocyte-endothelial cell interactions has not been defined. We observed that monocyte adhesion to resting or cytokine (tumor necrosis factor-alpha or interleukin-1 alpha)-stimulated human umbilical vein endothelial cells (HUVECs) was markedly inhibited (40 to 65%) by culture (1 to 6 days) of HUVECs with aFGF or bFGF. Monocyte transendothelial migration induced by C5a and chemokines (MCP-1, SDF-1 alpha, RANTES, MIP-1 alpha) was also suppressed (by 50 to 75%) on bFGF-stimulated HUVECs. VEGF did not have these effects at the concentrations used (10 to 20 ng/ml), although like bFGF, it promoted HUVEC proliferation. Culture of HUVECs with bFGF and aFGF significantly down-regulated intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin expression on resting or tumor necrosis factor-alpha-stimulated HUVECs, but had no influence on platelet endothelial cell adhesion molecule (PECAM)-1 and VE-cadherin expression. bFGF also inhibited MCP-1 production by HUVECs. The inhibitory effects of bFGF on monocyte transendothelial migration and adhesion molecule expression were reversed by SU6668, an anti-angiogenic agent and bFGF receptor tyrosine kinase inhibitor. Our results suggest that bFGF and aFGF may suppress endothelial-dependent monocyte recruitment and thus have an anti-inflammatory action during angiogenesis in chronic inflammation but inhibit the immunoinflammatory tumor defense mechanism. However, SU6668 is an effective agent to prevent this down-regulatory action of bFGF on monocyte-endothelial cell interactions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / pharmacology*
  • Antigens, CD
  • Cadherins / metabolism
  • Cell Adhesion
  • Cell Movement*
  • Cells, Cultured
  • Chemokine CCL2 / metabolism
  • Chemokine CCL4
  • Chemokine CCL5 / metabolism
  • Chemokine CXCL12
  • Chemokines, CXC / metabolism
  • Complement C5a / metabolism
  • Down-Regulation
  • E-Selectin / metabolism
  • Endothelial Growth Factors / physiology*
  • Endothelium, Vascular / cytology*
  • Endothelium, Vascular / drug effects
  • Enzyme-Linked Immunosorbent Assay
  • Fibroblast Growth Factor 1 / physiology*
  • Fibroblast Growth Factor 2 / physiology*
  • Humans
  • Indoles / pharmacology*
  • Intercellular Adhesion Molecule-1 / metabolism
  • Lymphokines / physiology*
  • Macrophage Inflammatory Proteins / metabolism
  • Monocytes / cytology*
  • Monocytes / drug effects
  • Platelet Endothelial Cell Adhesion Molecule-1 / metabolism
  • Pyrroles / pharmacology*
  • Vascular Cell Adhesion Molecule-1 / metabolism
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • Wound Healing

Substances

  • Angiogenesis Inhibitors
  • Antigens, CD
  • CXCL12 protein, human
  • Cadherins
  • Chemokine CCL2
  • Chemokine CCL4
  • Chemokine CCL5
  • Chemokine CXCL12
  • Chemokines, CXC
  • E-Selectin
  • Endothelial Growth Factors
  • Indoles
  • Lymphokines
  • Macrophage Inflammatory Proteins
  • Platelet Endothelial Cell Adhesion Molecule-1
  • Pyrroles
  • Vascular Cell Adhesion Molecule-1
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • cadherin 5
  • Fibroblast Growth Factor 2
  • Fibroblast Growth Factor 1
  • Intercellular Adhesion Molecule-1
  • Complement C5a
  • orantinib