Essential role for platelet-activating factor-induced NF-kappaB activation in macrophage-derived angiogenesis.
Activated monocyte-macrophages have been implicated in tumor angiogenesis via their capacity to produce many potent angiogenic factors. However, the mechanisms leading to production of these angiogenic factors in macrophages remain to be elucidated. In this study, we demonstrated by use of a mouse Matrigel implantation model that mouse peritoneal macrophages induce angiogenesis. mRNA expression and protein synthesis of macrophage-derived crucial angiogenic factors such as IL-1, TNF-alpha, basic fibroblast growth factor, and vascular endothelial growth factor (VEGF) were blocked by platelet-activating factor (PAF) receptor antagonists. It was also observed that inhibitors of NF-kappaB blocked macrophage production of these angiogenic factors. Gene expression and protein synthesis of the angiogenic factors cited above were also inhibited in IkappaBalpha-mutated macrophages. VEGF is the most potent angiogenic factor in macrophage-induced angiogenesis. PAF antagonists or NF-kappaB inhibitors also inhibit the capacity of conditioned medium from LPS-stimulated human peripheral blood monocytes to induce sprouting of porcine pulmonary arterial endothelial cells. These data indicate that PAF-induced NF-kappaB activation is a common upstream pathway leading to the production of crucial macrophage-derived angiogenic factors. This will provide an important clue for a better understanding of mechanisms involved in tumor angiogenesis.
Seo
Kook Heon
KH
Department of Biological Sciences, The Institute of Basic Sciences, Chonnam National University, Kwangju 500-757, Republic of Korea.
Ko
Hyun-Mi
HM
Choi
Jung Hwa
JH
Jung
Hae Hyun
HH
Chun
Young Hyun
YH
Choi
Il-Whan
IW
Lee
Hern-Ku
HK
Im
Suhn-Young
SY
D043925:Angiogenesis Inducing Agents / Q000276:immunology; D000818:Animals; D005260:Female; D006801:Humans; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D009000:Monocytes / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000378:metabolism*; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*
D043925:Angiogenesis Inducing Agents; D016328:NF-kappa B; D010972:Platelet Activating Factor