Rac, PAK, and eNOS ACTion

See related article, pages 360–368 Rac1 is a member of the Rho family of GTPases, which includes Rho, Rac, and cdc42 subfamilies.1,2 On activation by guanine nucleotide exchange factors, the Rho family GTPases exchange a GDP molecule for a GTP and act as molecular switches to transduce signals in response to various extracellular stimuli.2 Apart from their characteristic role in the regulation of cytoskeletal rearrangement and cell adhesion, the Rho family proteins have been found to regulate polarization, endocytosis, intracellular trafficking, cell cycle progression, differentiation, and gene transcription.1 Rho family GTPases play a role in endothelial permeability, polarization, leukocyte adhesion, and production of reactive oxygen species, including the superoxide anion (O![Graphic][1] 2).3–5 More specifically, activation of endothelial cells with growth factors such as vascular endothelial growth factor or by fluid shear stress has been shown to activate Rac1, which, in turn, promotes cytoskeletal rearrangement and changes in cell motility.6,7 Endothelial activation by growth factors or shear stress also results in the activation of NADPH oxidases (NOXs) and endothelial NO synthase (eNOS), which are responsible for the production of O![Graphic][2] 2 and NO, respectively.8–10 Because the modulation of endothelial NOXs by Rac1 has been well demonstrated,11–13 it is believed that Rac1 influences endothelial function, as measured by NO bioavailability, by enhancing the production of O![Graphic][3] 2 and not by direct modulation of eNOS. This assumes mutually exclusive mechanisms for the production of O![Graphic][4] 2 and NO and that a decreased bioavailability of NO on Rac1 activation is a result of O![Graphic][5] 2-dependent peroxynitrite production.8,14 Any association with or direct link between Rac1 activation and regulation of eNOS, therefore, has remained unexplored despite the observation that Rac1 and eNOS are both required for endothelial motility, proliferation, survival, and angiogenesis.6,7 The … [1]: /embed/inline-graphic-1.gif [2]: /embed/inline-graphic-2.gif [3]: /embed/inline-graphic-3.gif [4]: /embed/inline-graphic-4.gif [5]: /embed/inline-graphic-5.gif