Spare guanylyl cyclase NO receptors ensure high NO sensitivity in the vascular system
Evanthia Mergia, … , Michael Russwurm, Doris Koesling
Evanthia Mergia, … , Michael Russwurm, Doris Koesling
Published June 1, 2006
Citation Information: J Clin Invest. 2006;116(6):1731-1737. https://doi.org/10.1172/JCI27657.
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Research Article Vascular biology

Spare guanylyl cyclase NO receptors ensure high NO sensitivity in the vascular system

Abstract

In the vascular system, the receptor for the signaling molecule NO, guanylyl cyclase (GC), mediates smooth muscle relaxation and inhibition of platelet aggregation by increasing intracellular cyclic GMP (cGMP) concentration. The heterodimeric GC exists in 2 isoforms (α1-GC, α2-GC) with indistinguishable regulatory properties. Here, we used mice deficient in either α1- or α2-GC to dissect their biological functions. In platelets, α1-GC, the only isoform present, was responsible for NO-induced inhibition of aggregation. In aortic tissue, α1-GC, as the major isoform (94%), mediated vasodilation. Unexpectedly, α2-GC, representing only 6% of the total GC content in WT, also completely relaxed α1-deficient vessels albeit higher NO concentrations were needed. The functional impact of the low cGMP levels produced by α2-GC in vivo was underlined by pronounced blood pressure increases upon NO synthase inhibition. As a fractional amount of GC was sufficient to mediate vasorelaxation at higher NO concentrations, we conclude that the majority of NO-sensitive GC is not required for cGMP-forming activity but as NO receptor reserve to increase sensitivity toward the labile messenger NO in vivo.

Authors

Evanthia Mergia, Andreas Friebe, Oliver Dangel, Michael Russwurm, Doris Koesling

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Figure 4

Vasorelaxing properties of α-deficient aortic rings.

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Vasorelaxing properties of α-deficient aortic rings. Functional response...
Functional responses of aortic rings were determined as described in Methods. (A) Cumulative concentration-response curves of GSNO-induced relaxation of α1- and α2-deficient rings (n = 3 in each group). (B) GSNO-induced relaxation of WT and α1-deficient rings in the presence of the inhibitor of NO-sensitive GC, ODQ. Shown are the original recordings using 10 μM GSNO and 20 μM ODQ. ANP (10 nM) was added to confirm integrity of the rings. (C) NO-stimulated GC activities (100 μM DEA-NO) determined in aortic homogenates (n = 5 per genotype). (D) Carbachol-induced relaxation of WT and α-deficient aortic rings in the absence or presence of ODQ (n = 3–8 per genotype). Experiments used 30 μM carbachol and 20 μM ODQ.