Saying NO to Pressure

Abstract

Increases in arterial blood pressure stimulate vasoconstriction. In small cerebral arteries, this involves a graded depolarization in the membrane potential of arterial smooth muscle cells and the consequent influx of calcium through voltage-dependent calcium channels (VDCCs). Nuclear factor of activated T cells (NFAT), a transcription factor that undergoes translocation to the nucleus in response to sustained increases in intracellular calcium ([Ca 2+ ] i ), has been implicated in long-term cardiovascular processes such as vasculogenesis and cardiac hypertrophy. Gonzalez Bosc et al. used immunofluorescence microscopy to investigate possible effects of pressure on transcription and found that increased intraluminal pressure led to nuclear accumulation of NFATc3 in smooth muscle cells of isolated mouse cerebral arteries, which was inhibited by blockers of VDCCs. [This group previously found that Ca 2+ influx after depolarization with high concentrations of extracellular K + (HK) does not lead to nuclear accumulation of NFATc3 in cerebral vascular smooth muscle.] NFATc3 accumulation in response to pressure depended on endothelial cells [which produce nitric oxide (NO)]; pharmacological analysis indicated that accumulation depended on NO production and the ensuing activation of PKG [cyclic guanosine 3´,5´-monophosphate (cGMP)-dependent protein kinase] and was independent of vasoconstriction. (Indeed, NO and PKG promote smooth muscle relaxation.) Moreover, NO plus HK elicited nuclear accumulation of NFATc3. Increased pressure was associated with diminished phosphorylation of JNK2 (c-Jun N-terminal kinase 2, which promotes NFATc3 export from the nucleus), an effect that depended on PKG. In myocytes from mice that lacked JNK2, the effects of pressure were independent of PKG. Thus, in cerebral vascular smooth muscle, NO and Ca 2+ appear to enhance nuclear accumulation of NFAT cooperatively in response to pressure through respective effects on export and import. L. V. Gonzalez Bosc, M. K. Wilkerson, K. N. Bradley, D. M. Eckman, D. C. Hill-Eubanks, M. T. Nelson, Intraluminal pressure is a stimulus for NFATc3 nuclear accumulation. J. Biol. Chem. 279 , 10702-10709 (2004). [Abstract] [Full Text]