Regulation of endothelial cell branching morphogenesis by endogenous chemokine stromal-derived factor-1.
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.
Salvucci
Ombretta
O
Experimental Transplantation and Immunology Branch and the Laboratory of Pathology, National Cancer Institute, Bethesda, MD 20892, USA. salvucco@mail.nih.gov
Yao
Lei
L
Villalba
Sabrina
S
Sajewicz
Agatha
A
Pittaluga
Stefania
S
Tosato
Giovanna
G
D019898:Autocrine Communication / Q000187:drug effects; D018929:Cell Culture Techniques; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism / Q000494:pharmacology* / Q000502:physiology; D016228:Endothelial Growth Factors / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D005109:Extracellular Matrix / Q000502:physiology; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D008222:Lymphokines / Q000494:pharmacology; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects; D019718:Receptors, CXCR4 / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D014407:Tumor Cells, Cultured; D014470:Umbilical Cord / Q000166:cytology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D016228:Endothelial Growth Factors; D008222:Lymphokines; D019718:Receptors, CXCR4; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2