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Am J Physiol Gastrointest Liver Physiol 286: G1059-G1068, 2004. First published February 5, 2004; doi:10.1152/ajpgi.00417.2003
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INFLAMMATION/IMMUNITY/MEDIATORS

Mucosal angiogenesis regulation by CXCR4 and its ligand CXCL12 expressed by human intestinal microvascular endothelial cells

Jan Heidemann,1,2 Hitoshi Ogawa,1 Parvaneh Rafiee,3 Norbert Lügering,2 Christian Maaser,2 Wolfram Domschke,2 David G. Binion,1 and Michael B. Dwinell4

Departments of 1Medicine, 3Surgery, and 4Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin 53226; and 2Department of Medicine B, University of Münster, Münster 48149, Germany

Submitted 25 September 2003 ; accepted in final form 23 January 2004

Mice genetically deficient in the chemokine receptor CXCR4 or its ligand stromal cell-derived factor (SDF)-1/CXCL12 die perinatally with marked defects in vascularization of the gastrointestinal tract. The aim of this study was to define the expression and angiogenic functions of microvascular CXCR4 and SDF-1/CXCL12 in the human intestinal tract. Studies of human colonic mucosa in vivo and primary cultures of human intestinal microvascular endothelial cells (HIMEC) in vitro showed that the intestinal microvasculature expresses CXCR4 and its cognate ligand SDF-1/CXCL12. Moreover, SDF-1/CXCL12 stimulation of HIMEC triggers CXCR4-linked G proteins, phosphorylates ERK1/2, and activates proliferative and chemotactic responses. Pharmacological studies indicate SDF-1/CXCL12 evokes HIMEC chemotaxis via activation of ERK1/2 and phosphoinositide 3-kinase signaling pathways. Consistent with chemotaxis and proliferation, endothelial tube formation was inhibited by neutralizing CXCR4 or SDF-1/CXCL12 antibodies, as well as the ERK1/2 inhibitor PD-98059. Taken together, these data demonstrate an important mechanistic role for CXCR4 and SDF-1/CXCL12 in regulating angiogenesis within the human intestinal mucosa.

chemokine; intestinal vascularization; chemotaxis; proliferation


Address for reprint requests and other correspondence: M. B. Dwinell, Dept. of Microbiology and Molecular Genetics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226 (E-mail: mdwinell{at}mcw.edu).




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