Stimulation of the Na+/H+ exchanger in human endothelial cells activated by granulocyte- and granulocyte-macrophage-colony-stimulating factor. Evidence for a role in proliferation and migration

It has been shown that human endothelial cells (HEC) are stimulated to migrate and proliferate by granulocyte (G)- and granulocyte-macrophage (GM)-colony-stimulating factor (CSF) (Bussolino, F., Wang, J.M., Defilipii, P., Turrini, F., Sanavio, F., Edgell, C.-J. S., Aglietta, M., Arese, P., and Mantovani, A. (1989) Nature 337, 471-473). The rapid intracellular events initiated by these cytokines on binding to their receptors of HEC are not defined. Addition of G- or GM-CSF to HEC produced a rapid activation of Na⁺/H⁺ exchanger resulting in an increase in intracellular pH (pH(i)). Both cytokines induced an alkaline displacement in the pH(i) dependence of the exchanger without affecting the affinity for external Na⁺ (Na(o)) and the rate of exchanger. Ethylisopropylamiloride, a selective inhibitor of the Na⁺/H⁺ exchanger, inhibited the intracellular alkalinization, the migration, and proliferation induced by G- and GM-CSF. The data indicate that G- and GM-CSF initiate a rapid exchange of Na⁺ and H⁺ by means of the Na⁺/H⁺ exchanger and that this ethylisopropylamiloride-sensitive ions flux is important to the biological effects of these cytokines on HEC.