The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract

Abstract

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 mice. 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 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 formation. CXCR4 also functions as a co-receptor for T-cell-line tropic human immunodeficiency virus HIV-1. 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.

CXCR4/CXCL12 expression and signalling in kidney cancer

“…The functions of CXCR4 have not yet been fully understood, but it appears that it mediates a large variety of functions including leukocyte development and trafficking, HIV-infection, correct foetal vascularisation and CNS development and possibly cell division, tumourigenesis and growth (Tachibana et al, 1998;Zou et al, 1998;Gabuzda and Wang, 1999). Rempel et al (2000) observed a tumour grade-dependent surge of CXCR4 mRNA levels in glioblastoma multiforme and that this receptor is mainly expressed in regions of angiogenesis and degenerative, necrotic, and microcystic changes rather than in sections of rapid cell proliferation.…”

Epigenetic silencing of CXCL12 increases the metastatic potential of mammary carcinoma cells

“…The constitutive chemokine ligand CXCL12 and its cognate receptor CXCR4 are evolutionarily conserved and essential for life in mice (Nagasawa et al, 1996a, b). Homeostatic roles for CXCL12 signaling through CXCR4 in various physiological compartments have been described, including B-cell development, gastrointestinal vascularization, heart and cerebral development, as well as mucosal epithelial wound healing (Nagasawa et al, 1996a;Tachibana et al, 1998;Zou et al, 1998;Heidemann et al, 2003;Smith et al, 2005;Moyer et al, 2007). Thus, CXCL12 and CXCR4 are widely expressed throughout the body and serve diverse physiological roles depending on the tissue or cell type.…”

CXCR4 modulates contractility in adult cardiac myocytes

“…CXCR4 exemplifies this concept. It is present on the mammalian heart and appears to play a critical role in cardiovascular development, in the mobilization of hematopoietic precursors and in vasculogenesis [3,4]. CXCR4 is also a coreceptor for HIV infection and can modulate Ca 2+ channel function in neuronal cell lines [5].…”