Regulation of endothelial cell branching morphogenesis by endogenous chemokine stromal-derived factor-1

Blood. 2002 Apr 15;99(8):2703-11. doi: 10.1182/blood.v99.8.2703.

Abstract

The chemokine stromal-derived factor-1 (SDF-1) and its unique receptor, CXCR4, are required for normal cardiovascular development, but a critical role for SDF-1 in postnatal vascular remodeling and the mechanisms underlying SDF-1/CXCR-4 vasculogenesis are unclear. Here we show that SDF-1 is expressed by the vascular endothelium from selected healthy and tumor tissues. In vitro, primary endothelial cells constitutively express SDF-1 that is detected in the cytoplasm, on the cell surface, and in the culture supernatant. Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) increase SDF-1 expression in endothelial cells. In functional studies, pertussis toxin and antibodies to SDF-1 or CXCR-4 disrupt extracellular matrix-dependent endothelial cell tube formation in vitro. This morphogenic process is associated with time-dependent modulation of surface CXCR-4 expression that changes from being diffuse to being polarized and subsequently lost. In vivo, pertussis toxin and neutralizing antibodies directed at SDF-1 inhibit growth factor-dependent neovascularization. These results indicate that SDF-1/CXCR-4 identifies VEGF- and bFGF-regulated autocrine signaling systems that are essential regulators of endothelial cell morphogenesis and angiogenesis.

MeSH terms

  • Autocrine Communication / drug effects
  • Cell Culture Techniques
  • Chemokine CXCL12
  • Chemokines, CXC / metabolism
  • Chemokines, CXC / pharmacology*
  • Chemokines, CXC / physiology
  • Endothelial Growth Factors / pharmacology
  • Endothelium, Vascular / cytology*
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism
  • Extracellular Matrix / physiology
  • Fibroblast Growth Factor 2 / pharmacology
  • Gene Expression Regulation / physiology
  • Humans
  • Lymphokines / pharmacology
  • Neovascularization, Pathologic / metabolism
  • Neovascularization, Pathologic / pathology
  • Neovascularization, Physiologic / drug effects
  • Receptors, CXCR4 / drug effects
  • Receptors, CXCR4 / metabolism
  • Receptors, CXCR4 / physiology
  • Tumor Cells, Cultured
  • Umbilical Cord / cytology
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors

Substances

  • CXCL12 protein, human
  • Chemokine CXCL12
  • Chemokines, CXC
  • Endothelial Growth Factors
  • Lymphokines
  • Receptors, CXCR4
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • Fibroblast Growth Factor 2