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Received for publication January 13, 2005.
Revised March 16, 2005.
Accepted for publication March 17, 2005.
Classically, nitric oxide (NO) formed by endothelial NO synthase (eNOS) freely diffuses from its generation site to smooth muscle cells where it activates soluble guanylyl cyclase (sGC) producing guanosine 3'5'cyclic monophosphate (cGMP). Subsequently, cGMP activates both cGMP- and adenosine 3'5'cyclic monophosphate (cAMP)-dependent protein kinases (PKG and PKA, respectively) leading to smooth muscle relaxation. In endothelial cells, eNOS has been localized to caveolae, small invaginations of the plasma membrane rich in cholesterol. Membrane cholesterol depletion impairs acetylcholine (Ach)-induced relaxation due to alteration in caveolar structure. Given the nature of NO to be more soluble in a hydrophobic environment than in water, and assuming that co-localization of components in a signal transdution cascade appears to be a critical determinant of signaling efficiency by eNOS activation, we hypothesize that sGC, PKA and PKG activation may occur at the plasma membrane caveolae. In endothelium-intact rat aortic rings, the relaxation induced by ACh-, by the sGC activator 3-(5'-hydroxymethyl-2'furyl)-1-benzyl indazole (YC-1) and by 8-Bromoguanosine 3': 5'-cyclic monophosphate (8-Br-cGMP) was impaired in the presence of methyl-
-cyclodextrin, a drug that disassembles caveolae by sequestering cholesterol from the membrane. sGC, PKG and PKA were co-localized with caveolin-1 in aortic endothelium and this co-localization was abolished by methyl--cyclodextrin. Methyl--cyclodextrin efficiently disassembled caveolae in endothelium. In summary, our results provide evidence of compartmentalization of sGC, PKG and PKA in endothelial caveolae contributing to NO signaling cascade giving new insights by which the endothelium mediates vascular smooth muscle relaxation.
Key words:
cAMP-dependent protein kinase, cGMP, caveolin-1, endothelium, smooth muscle, vasodilation
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