Vascularization of organs generally occurs by remodelling of the preexisting vascular system during their differentiation and growth to enable them to perform their specific functions during development. The molecules required by early vascular systems, many of which are receptor tyrosine kinases and their ligands, have been defined by analysis of mutant mice1,2,3. As most of these mice die during early gestation before many of their organs have developed, the molecules responsible for vascularization during organogenesis have not been identified. The cell-surface receptor CXCR4 (4–6) is a seven-transmembrane-spanning, G-protein-coupled receptor for the CXC chemokine PBSF/SDF-1 (for pre-B-cell growth-stimulating factor/stromal-cell-derived factor), which is responsible for B-cell lymphopoiesis, bone-marrow myelopoiesis and cardiac ventricular septum formation7. CXCR4 also functions as a co-receptor for T-cell-line tropic human immunodeficiency virus HIV-1 (ref. 8). Here we report that CXCR4 is expressed in developing vascular endothelial cells, and that mice lacking CXCR4 or PBSF/SDF-1 have defective formation of the large vessels supplying the gastrointestinal tract. In addition, mice lacking CXCR4 die in utero and are defective in vascular development, haematopoiesis and cardiogenesis, like mice lacking PBSF/SDF-1, indicating that CXCR4 is a primary physiological receptor for PBSF/SDF-1. We conclude that PBSF/SDF-1 and CXCR4 define a new signalling system for organ vascularization.
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Risau, W. Mechanisms of angiogenesis. Nature 386, 671–674 (1997).
Folkman, J. & D'Amore, P. A. Blood vessel formation: what is its molecular basis? Cell 87, 1153–1155 (1996).
Lindahl, P., Johansson, B. R., Leveen, P. & Betsholtz, C. Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science 277, 242–245 (1997).
Bleul, C. C.et al. The lymphocyte chemoattractant SDF-1 is a ligand for LESTR/fusin and blocks HIV-1 entry. Nature 382, 829–833 (1996).
Oberlin, E.et al. The CXC chemokine SDF-1 is the ligand for LESTR/fusin and prevents infection by T-cell-line-adapted HIV-1. Nature 382, 833–835 (1996).
Nagasawa, T.et al. Molecular cloning and characterization of a murine pre-B-cell growth-stimualting factor/stromal cell-derived factor 1 receptor, a murine homolog of the human immunodeficiency virus 1 entry coreceptor fusin. Proc. Natl Acad. Sci. USA 93, 14726–14729 (1996).
Nagasawa, T.et al. Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature 382, 635–638 (1996).
Feng, Y., Broder, C. C., Kennedy, P. E. & Berger, E. A. HIV-1 entry corecptor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science 272, 872–877 (1996).
Baggiolini, M., Dewald, B. & Moser, B. Human chemokines: an update. Annu. Rev. Immunol. 15, 675–705 (1997).
Vecchi, A.et al. Monoclonal antibodies specific for endothelial cells of mouse blood vessels. Their application in the identification of adult and embryonic endothelium. Eur. J. Cell Biol. 63, 247–255 (1994).
Baldwin, H. S.et al. Platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31): alternatively spliced, functionally distinct isoforms expressed during mammalian cardiovascular development. Development 120, 2539–2553 (1994).
Shalaby, F.et al. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nautre 376, 62–66 (1995).
Fong, G.-H., Rossant, J., Gertsenstein, M. & Breitman, M. L. Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature 376, 66–70 (1995).
Dumont, D. J.et al. Dominant-negative and targeted null mutations in the endothelial receptor tyrosine kinase, tek, reveal a critical role in vasculogenesis of the embryo. Genes Dev. 8, 1897–1909 (1994).
Sato, T. N.et al. Distinct roles of the receptor tyrosine kinases Tie-1 and Tie-2 in blood vessel formation. Nature 376, 70–74 (1995).
Carmeliet, P.et al. Abnormal blood vessel development and lethality in embryos lacking a single vEGF allele. Nature 380, 435–439 (1996).
Ferrara, N.et al. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 380, 439–442 (1996).
Suri, C.et al. Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell 87, 1171–1180 (1996).
Maione, T. E.et al. Inhibition of angiogenesis by recombinant human platelet factor-4 and related peptides. Science 247, 77–79 (1990).
Koch, A. E.et al. Interleukin-8 as a macrophage-derived mediator of angiogenesis. Science 258, 1798–1801 (1992).
Luster, A. D., Greenberg, S. M. & Leder, P. The IP-10 chemokine bind to a specific cell surface heparan sulfate site shared with platelet factor 4 and inhibits endothelial cell proliferation. J. Exp. Med. 182, 219–231 (1995).
Cao, Y., Chen, C., Weatherbee, J. A., Tsang, M. & Folkman, J. gro-β, a CXC chemokine, is an angiogenesis inhibitor that suppresses the growth of Lewis lung carcinoma in mice. J. Exp. Med. 182, 2069–2077 (1995).
Cui, J., Sue O'Shea,, Purkayastha, A., Saunders, T. L. & Ginsburg, D. Fatal haemorrhage and incomplete block ot embryogenesis in mice lacking coagulation factor V. Nature 384, 66–68 (1996).
Carmeliet, P.et al. Role of tissue factor in embryonic blood vessel development. Nature 383, 73–75 (1996).
Offermanns, S., Mancino, V., Revel, J.-P. & Simon, M. I. Vascular system defects and impaired cell chemokinesis as a result of Gα13deficiency. Science 275, 533–535 (1997).
Fauci, A. S. Host factors and the pathogenesis of HIV-induced disease. Nature 384, 529–535 (1996).
Liu, R.et al. Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection. Cell 86, 367–377 (1996).
Samson, M.et al. Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of the R-5 chemokine receptor gene. Nature 382, 722–725 (1996).
Dean, M.et al. Genetic restriction of HIV-1 infection and progression to AIDS by a detection allele of the CCR5 structural gene. Science 273, 1856–1861 (1996).
Adachi, S., Yoshida, H., Kataoka, H. & Nishikawa, S.-I. Three distinctive steps in Peyer's patch formation of murine embryo. Int. Immunol. 9, 507–514 (1997).
We thank K. Morihana, T. Ohito and T. Iwaki for technical assistance; T. Tanaka for technical advice; and T. Nakajima for discussion. This work was supported by grants from the Ministry of Education of Japan.
About this article
Cite this article
Tachibana, K., Hirota, S., Iizasa, H. et al. The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract. Nature 393, 591–594 (1998) doi:10.1038/31261
Atypical Chemokine Receptor 3 Generates Guidance Cues for CXCL12-Mediated Endothelial Cell Migration
Frontiers in Immunology (2019)
Dorsal-to-Ventral Cortical Expansion Is Physically Primed by Ventral Streaming of Early Embryonic Preplate Neurons
Cell Reports (2019)
An injectable scaffold based on temperature‐responsive hydrogel and factor‐loaded nanoparticles for application in vascularization in tissue engineering
Journal of Biomedical Materials Research Part A (2019)
Frontiers in Immunology (2019)