VEGF₁₆₄ differentially regulates neutrophil and T cell adhesion through ItgaL- and ItgaM-dependent mechanisms.
Leukocyte recruitment to inflamed tissues is the cornerstone of inflammatory responses and the driving force behind the establishment of inflammatory bowel disease, consisting of Crohn's disease and ulcerative colitis. It has been reported that angiogenic cytokines contribute to this inflammatory response that facilitates the chronic nature of disease. We have previously reported (Goebel S, Huang M, Davis WC, Jennings M, Siahaan TJ, Alexander JS, Kevil CG. Am J Physiol Gastrointest Liver Physiol 290: G648-G654, 2006) that vascular endothelial growth factor (VEGF)-A can stimulate neutrophil adhesion to colon microvascular endothelial cells in a β₂-integrin (Itgb2)-dependent manner. However, it is not known which of the specific leukocyte integrins are critical for VEGF-A-dependent neutrophil and T cell recruitment. Here we examine the differential importance of either α-integrin (Itga)L or ItgaM in governing neutrophil and T cell adhesion to VEGF-A-activated colonic endothelium. Using an in vitro parallel-plate flow chamber model, we found that genetic deficiency of ItgaM completely blunted neutrophil adhesion to VEGF-A-stimulated endothelium, whereas ItgaL deficiency only partly blocked neutrophil adhesion. Deficiency of ItgaM did significantly decrease neutrophil rolling, whereas deficiency of ItgaL did not. We found that genetic deficiency of either ItgaL or ItgaM did significantly blunt T cell adhesion to VEGF-A-stimulated colon endothelium. We also found that genetic deficiency of these Itgas significantly attenuated T cell rolling behavior. Lastly, we examined whether VEGF-A-mediated leukocyte recruitment occurred through different VEGF receptor (VEGFR) pathways and found that VEGFR2 activation regulates neutrophil recruitment, whereas both VEGFR1 and VEGFR2 modulate T cell recruitment. Together, these data identify differential molecular mechanisms of VEGF-A-mediated leukocyte recruitment.
Chidlow
John H
JH
Dept. of Pathology, LSUHSC, Shreveport, LA 71130, USA.
Glawe
John D
JD
Alexander
J Steven
JS
Kevil
Christopher G
CG
D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D040881:CD11a Antigen / Q000235:genetics / Q000378:metabolism*; D039481:CD11b Antigen / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion; D002460:Cell Line; D003106:Colon / Q000502:physiology; D004727:Endothelium / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D008024:Ligands; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000502:physiology*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
D040881:CD11a Antigen; D039481:CD11b Antigen; D008024:Ligands; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D040262:Receptors, Vascular Endothelial Growth Factor