Podokinesis in endothelial cell migration: role of nitric oxide

Abstract

Previously, we demonstrated the role of nitric oxide (NO) in transforming epithelial cells from a stationary to locomoting phenotype [E. Noiri, T. Peresleni, N. Srivastava, P. Weber, W. F. Bahou, N. Peunova, and M. S. Goligorsky. Am. J. Physiol. 270 ( Cell Physiol. 39): C794–C802, 1996] and its permissive function in endothelin-1-stimulated endothelial 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 present study, the role of functional NO synthase in executing the vascular endothelial growth factor (VEGF)-guided program of endothelial cell migration and angiogenesis was studied in two independent experimental settings. First, VEGF, shown to stimulate NO release from simian virus 40-immortalized microvascular endothelial cells, induced endothelial cell transwell migration, whereas N G-nitro-l-arginine methyl ester (l-NAME) or antisense oligonucleotides to endothelial NO synthase suppressed this effect of VEGF. Second, in a series of experiments on endothelial cell wound healing, the rate of VEGF-stimulated cell migration was significantly blunted by the inhibition of NO synthesis. To gain insight into the possible mode of NO action, we next addressed the possibility that NO modulates cell matrix adhesion by performing impedance analysis of endothelial cell monolayers subjected to NO. The data showed the presence of spontaneous fluctuations of the resistance in ostensibly 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 micromotion that, in the presence of guidance cues, e.g., VEGF, is transformed to a vectorial movement. In conclusion, execution of the program for directional endothelial cell migration requires two coexisting messages: NO-induced podokinesis (scalar motion) and guidance cues, e.g., VEGF, which imparts a vectorial component to the movement. Such a requirement for the dual signaling may explain a mismatch in the demand and supply with newly formed vessels in different pathological states accompanied by the inhibition of NO synthase.

Stromal Cell-Derived Factor 1α-Induced Chemotaxis in T Cells Is Mediated by Nitric Oxide Signaling Pathways

“…NO has been shown to have opposing and complex effects on chemotactic responses exerted by various stimuli. For example, it has been shown that NO enhances chemotactic responses in some cell types (45,46,(61)(62)(63) upon certain stimuli, while inhibiting cell migration in others (47,64). Furthermore, NO has been shown to modulate T cell chemotaxis in Peyer's patches and in the nonlymphoid region of the intestine (65).…”

Angiogenic Actions of Angiopoietin-1 Require Endothelium-Derived Nitric Oxide

“…Moreover, a number of reports suggest that NO mediates the angiogenic activity of several angiogenic growth factors including TGF-␤, bFGF, and VEGF. 24,27,49 EC proliferation, 24,50,51 migration, 50,52 and tube formation 24 in response to VEGF in vitro could be inhibited by the addition of NOS inhibitors to the cultured EC. Also, experiments using systemic inhibition of NOS 53 or eNOS KO animals 26 have provided evidence supporting an important role for NO in VEGF-induced angiogenesis in vivo.…”

The Role of Vascular Endothelial Growth Factor in Wound Healing

“…It functions as an endothelial cell mitogen [12][13][14][15][16][17] , chemotactic agent 18,19 , and inducer of vascular permeability 20,21,[22][23][24][25][26] . Other angiogenic growth factors such as basic fibroblast growth factor (bFGF) and transforming growth factor β (TGF-β) have been described, but VEGF is unique for its effects on multiple components of the wound healing cascade, including angiogenesis and recently shown epithelization and collagen deposition.…”