Functional role of the soluble guanylyl cyclase α1 subunit in vascular smooth muscle relaxation

Abstract

Objective: Soluble guanylyl cyclase (sGC), the predominant receptor for nitric oxide (NO), exists in 2 active isoforms (α2β1 and α1β1). In vascular tissue sGCα1β1 is believed to be the most important. The aim of our study was to investigate the functional importance of the sGCα1-subunit in vasorelaxation. Methods: Aortic and femoral artery segments from male and/or female sGCα1−/− mice and wild-type littermates were mounted in a small-vessel myograph for isometric tension recording. This was supplemented with biochemical measurements of the cGMP concentration and sGC enzyme activity. Results: The functional importance of sGCα1β1 was demonstrated by the significantly decreased relaxing effects of acetylcholine (ACh), sodium nitroprusside (SNP), S-nitroso-N-acetylpenicillamine (SNAP), NO gas, YC-1, BAY 41-2272 and T-1032 in the sGCα1−/− mice of both genders. Moreover, the basal and SNP-stimulated cGMP levels and basal sGC activity were significantly lower in the sGCα1−/− mice. However, the relaxing effects of NO, BAY 41-2272 and YC-1 seen in blood vessels from sGCα1−/− mice indicate a role for an sGCα1β1-independent mechanism. The increase in sGC activity after addition of BAY 41-2272 and the inhibition of the ACh-, SNP-, SNAP- and NO gas-induced response by the sGC inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) in the sGCα1−/− mice are observations suggesting that the sGCα2β1 isoform is also functionally active. However, the insignificant increase in cGMP in response to SNP and the non-upregulated sGCα2 expression level in the sGCα1−/− mice suggest rather the involvement of (an) sGC-independent mechanism(s). Conclusions: We conclude that sGCα1β1 is involved in the vasorelaxation induced by NO-dependent and NO-independent sGC activators in both genders. However, the remaining relaxation seen in the sGCα1−/− mice suggests that besides sGCα1β1 also the minor isoform sGCα2β1 and/or (an) sGC-independent mechanism(s) play(s) a substantial role.