CXCR4 on human endothelial cells can serve as both a mediator of biological responses and as a receptor for HIV-2.
It has been shown that deletion of the chemokine receptor, CXCR4, causes disordered angiogenesis in mouse models. In the present studies, we examined the distribution and trafficking of CXCR4 in human endothelial cells, tested their responses to the CXCR4 ligand, SDF-1, and asked whether endothelial cell CXCR4 can serve as a cell surface receptor for the binding of viruses. The results show that CXCR4 is present on endothelial cells from coronary arteries, iliac arteries and umbilical veins (HUVEC), but expression was heterogeneous, with some cells expressing CXCR4 on their surface, while others did not. Addition of SDF-1 caused a rapid decrease in CXCR4 surface expression. It also caused CXCR4-mediated activation of MAPK, release of PGI(2), endothelial migration, and the formation of capillary-like structures by endothelial cells in culture. Co-culture of HUVEC with lymphoid cells that were chronically infected with a CD4-independent/CXCR4-tropic variant of HIV-2 resulted in the formation of multinucleated syncytia. Formation of the syncytia was inhibited by each of several different CXCR4 antibodies. Thus, our findings indicate: (1) that CXCR4 is widely expressed on human endothelial cells; (2) the CXCR4 ligand, SDF-1, can evoke a wide variety of responses from human endothelial cells; and (3) CXCR4 on endothelial cells can serve as a receptor for isolates of HIV that can utilize chemokine receptors in the absence of CD4.
Molino
M
M
Consorzio Mario Negri Sud, Santa Maria Imbaro, Italy.
Woolkalis
M J
MJ
Prevost
N
N
Praticó
D
D
Barnathan
E S
ES
Taraboletti
G
G
Haggarty
B S
BS
Hesselgesser
J
J
Horuk
R
R
Hoxie
J A
JA
Brass
L F
LF
D019380:Anti-HIV Agents / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects; D002196:Capillaries / Q000166:cytology; D002459:Cell Fusion / Q000187:drug effects; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects; D003094:Collagen; D003331:Coronary Vessels / Q000166:cytology; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D015536:Down-Regulation; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000821:virology; D011464:Epoprostenol / Q000378:metabolism; D005434:Flow Cytometry; D015870:Gene Expression; D015498:HIV-2 / Q000502:physiology*; D006801:Humans; D007083:Iliac Artery / Q000166:cytology; D007124:Immunoenzyme Techniques; D007797:Laminin; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008856:Microscopy, Fluorescence; D009024:Morphogenesis / Q000187:drug effects; D011509:Proteoglycans; D020239:Receptor Cross-Talk; D044463:Receptor, PAR-1; D019718:Receptors, CXCR4 / Q000235:genetics / Q000502:physiology*; D018179:Receptors, Thrombin / Q000502:physiology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014471:Umbilical Veins / Q000166:cytology
D019380:Anti-HIV Agents; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D044463:Receptor, PAR-1; D019718:Receptors, CXCR4; D018179:Receptors, Thrombin; C059485:matrigel; D003094:Collagen; D011464:Epoprostenol; D013755:Tetradecanoylphorbol Acetate