Negative feedback regulation within NO/cGMP pathway attenuates vasodilatory response in renovascular hypertension

Background Hypertension, the leading risk factor for cardiovascular mortality has been associated with alterations in endotheliumand smooth muscle-dependent vascular relaxation. The NO/cGMP signaling cascade is one of the major pathways that mediate vascular relaxation. In this pathway, the NO receptor guanylyl cyclase (NO-GC) holds a key position by converting the NO signal into cGMP increases. Two isoforms of the heterodimeric NO receptor GC exist; both isoforms share an identical β subunit but differ in their respective α subunit (α1 or α2) and are referred to as NO-GC1 (so far α1β1heterodimer) and NO-GC2 (so far α2β1heterodimer), respectively. Knockout (KO) mice deficient in either one of the NO-GCs, NO-GC1 or NO-GC2, revealed that both NO-GCs are capable to mediate vascular relaxation. The NO-GC1 appears to be the major isoform, particularly in the aorta, where NO-GC1 represents approximately 90% of total NO-GC content. Deletion of the NO-GC1 resulted in reduced endothelium-dependent relaxation and reduced vasodilatory response to exogenous NO, which is mediated by the NO receptor GC2 in NO-GC1-deficient mice. Despite the low NO-GC2 content, NO-GC1 KO mice exhibit only a minute blood pressure increase.