Anti-angiogenic effects of imatinib target smooth muscle cells but not endothelial cells.
Knowing that progesterone up-regulates PDGF-A, which plays a relevant role in angiogenesis, and that imatinib mesylate targets PDGF receptor tyrosine kinase activity, the aim of the present study was to examine the effects of imatinib on Human Aortic Smooth Muscle Cells (HAoSMC) and Human Umbilical Vein Endothelial Cells (HUVEC) after incubation with progesterone. Expression of phosphorylated (activated) PDGFR-alpha was detected in HAoSMC, but in a very low extent in HUVEC. In agreement with the lack of active PDGFR-alpha, imatinib was unable to prevent HUVEC growth, survival or migration ability. In contrast, HAoSMC viability and proliferation were effectively inhibited by imatinib, as evaluated by MTT and BrdU incorporation assay, respectively. Corroborating these findings, a significant increase in the percentage of apoptotic cells was also observed after treatment with imatinib. Cell migration assays also showed a reduction in the migratory ability after incubation with imatinib. Altogether, these facts reveal that imatinib is able to affect HAoSMC survival, growth and migration. Furthermore, incubation with recombinant PDGF as well as, with progesterone seems to sustain PDGFR-alpha activity, prompting these cells to the inhibitory action of imatinib. These findings were restricted to smooth muscle cells, leading to the assumption that imatinib is probably preventing vessel stabilization, a crucial event for neovascular maturation. Our findings indicate that imatinib might be a good therapeutic agent against atherosclerosis and other vascular-associated disorders that carry in common smooth muscle cells abnormal growth.
Rocha
Ana
A
Department of Biochemistry (U38-FCT), Faculty of Medicine, University of Porto, Al. Prof. Hernâni Monteiro, 4200-319 Porto, Portugal.
Azevedo
Isabel
I
Soares
Raquel
R
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D001549:Benzamides; D015153:Blotting, Western; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D000068877:Imatinib Mesylate; D020287:In Situ Nick-End Labeling; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D018919:Neovascularization, Physiologic; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*
D020533:Angiogenesis Inhibitors; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate