Mucosal angiogenesis regulation by CXCR4 and its ligand CXCL12 expressed by human intestinal microvascular endothelial cells.
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.
Heidemann
Jan
J
Deptartment of Medicine, Medical College of Wisconsin, Milwaukee, 53226, USA.
Ogawa
Hitoshi
H
Rafiee
Parvaneh
P
Lügering
Norbert
N
Maaser
Christian
C
Domschke
Wolfram
W
Binion
David G
DG
Dwinell
Michael B
MB
D001672:Biocompatible Materials; D002455:Cell Division / Q000502:physiology; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000502:physiology*; D002633:Chemotaxis / Q000502:physiology; D003094:Collagen; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D007413:Intestinal Mucosa / Q000098:blood supply*; D007797:Laminin; D008024:Ligands; D008833:Microcirculation; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000502:physiology*; D010766:Phosphorylation; D011509:Proteoglycans; D019718:Receptors, CXCR4 / Q000502:physiology*
D001672:Biocompatible Materials; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D004338:Drug Combinations; D007797:Laminin; D008024:Ligands; D011509:Proteoglycans; D019718:Receptors, CXCR4; C059485:matrigel; D003094:Collagen; D020928:Mitogen-Activated Protein Kinases