DIFFERENCES IN ANGIOGENIC POTENTIAL OF CLASSICALLY VS ALTERNATIVELY ACTIVATED MACRO PHAGES

Macrophages (M Phi) are important for angiogenesis during inflammation , wound repair, and tumor growth. However, well-characterized M Phi su bsets such as IFN-gamma-induced, classically activated (ca) M Phi or I L-4/glucocorticoid-induced, alternatively activated (aa) M Phi, have n ot been thoroughly examined for a positive or negative association wit h angiogenesis. While caM Phi populate early inflammatory reactions an d high-turnover granulomas, aaM Phi occur in healing wounds and chroni c inflammation. In contrast to caM Phi-dominated lesions, aaM Phi-rich lesions are highly vascularized. In order to determine their angiogen eic potential in vitro, these M Phi subsets as well as unstimulated co ntrol macrophages (coM Phi) were analyzed by RT-PCR for mRNA expressio n of 10 angiogenic factors after 3 and 6 days of culture. Early during activation, caM Phi, and coM Phi expressed equal levels of 8 of 10 an giogenic factors (PDGF-A, MK, TNF-alpha, TGF-beta(1), PDGF-B, HGF, TGF -alpha, IGF-1), while aaM Phi showed expression of only 4 of these fac tors (TGF-beta(1), PDGF-B, HGF, GF-1). After maturation, TGF-alpha and IGF-1 showed a shift in mRNA expression from caM Phi to aaM Phi resul ting in a considerably enhanced expression of these factors in day-6 a aM Phi as compared to day-6 caM Phi and coM Phi while PDGF-A, MK, and TNF-alpha remained suppressed in day 6 aaM Phi. In all M Phi subsets i ncluding controls, mRNA expression of aFGF and bFGF was minimal or abs ent while TGFG-beta(1), HGF, and ODGF-B were constitutively expressed. In order to functionally integrate angiogenic factor mRNA expression profiles, mitogenic activity of M Phi, subsets towards microvascular e ndothelium was assessed by cocultivation. Coculture experiments reveal ed that endothelial proliferation induced by aaM Phi was 3.0-3.5x high er than induced by caM Phi. In conclusion. mature aaM Phi are well equ ipped to play an important role in protracted M Phi-associated angioge nic processes. Presumably due to expression of predominantly angioinhi bitory cytokines such as TNF-alpha by caM Phi but much less by aaM Phi , caM Phi exhibit only a low angiogenic potential in vitro and in vivo despite considerable expression of angiogenic factor mRNA.