PODOKINESIS IN ENDOTHELIAL-CELL MIGRATION - ROLE OF NITRIC-OXIDE

Previously, we demonstrated the role of nitric oxide (NO) in transform ing epithelial cells from a stationary to locomoting phenotype [E. Noi ri, T. Peresleni, N. Srivastava, P. Weber, W. F. Bahou, N. Peunova, an d M. S. Goligorsky. Am. J. Physiol. 270 (Cell Physiol. 39): C794-C802, 1996] and its permissive function in endothelin-1-stimulated endothel ial cell migration (E. Noiri, Y. Hu, W. F. Bahou, C. Keese, I. Giaever , and M. S. Goligorsky. J. Biol. Chem. 272: 1747-1753, 1997). In the p resent study, the role of functional NO synthase in executing the vasc ular endothelial growth factor (VEGF)-guided program of endothelial ce ll migration and angiogenesis was studied in two independent experimen tal settings. First, VEGF, shown to stimulate NO release from simian v irus 40-immortalized microvascular endothelial cells, induced endothel ial cell transwell migration, whereas N-G-nitro-L-arginine methyl este r (L-NAME) or antisense oligonucleotides to endothelial NO synthase su ppressed this effect of VEGF. Second, in a series of experiments on en dothelial cell wound healing, the rate of VEGF-stimulated cell migrati on was significantly blunted by the inhibition of NO synthesis. To gai n insight into the possible mode of NO action, we next addressed the p ossibility that NO modulates cell matrix adhesion by performing impeda nce analysis of endothelial cell monolayers subjected to NO. The data showed the presence of spontaneous fluctuations of the resistance in o stensibly stationary endothelial cells. Spontaneous oscillations were induced by NO, which also inhibited cell matrix adhesion. This process we propose to term ''podokinesis'' to emphasize a scalar form of micr omotion that, in the presence of guidance cues, e.g., VEGF, is transfo rmed to a vectorial movement. In conclusion, execution of the program for directional endothelial cell migration requires two coexisting mes sages: NO-induced podokinesis (scalar motion) and guidance cues, e.g., VEGF, which imparts a vectorial component to the movement. Such a req uirement for the dual signaling may explain a mismatch in the demand a nd supply with newly formed vessels in different pathological states a ccompanied by the inhibition of NO synthase.