Soluble Guanylate Cyclase Modulators in Vascular Function

Soluble guanylate cyclase (sGC) is the principal receptor for nitric oxide (NO) in the vasculature, converting guanosine triphosphate into cyclic guanosine monophosphate (cGMP) to promote vasodilation, inhibit platelet aggregation and attenuate vascular remodelling. Under physiological conditions, NO binds to the ferrous (Fe2+) heme moiety of sGC to trigger a conformational change that enhances cGMP synthesis. Oxidative stress, however, oxidises the heme to the ferric (Fe3+) state or leads to heme loss, producing apo-sGC forms that are unresponsive to NO. To overcome this, two classes of pharmacological agents have been developed: sGC stimulators, which act on the native ferrous enzyme and synergise with NO, and sGC activators, which target the oxidised or heme-free enzyme independently of NO. Collectively, these modulators restore NO-cGMP signalling in diverse cardiovascular and cerebrovascular disorders, offering anti-hypertensive, anti-inflammatory and anti-fibrotic benefits.

Research from Nature Portfolio

A genetically engineered mouse model expressing haem-free sGC (apo-sGC mice) has provided critical insight into the in vivo consequences of heme oxidation. These animals develop hypertension and lose NO-induced vasorelaxation, yet display enhanced responsiveness to sGC activators. The study demonstrates that loss of the prosthetic heme group abolishes NO-mediated blood pressure control but unmasks the therapeutic potential of activators that bind and activate oxidised or haem-free enzyme. Importantly, this work establishes apo-sGC mice as a platform to distinguish between sGC-dependent and independent NO effects, and to evaluate next-generation activators in models of cardiovascular dysfunction.

Research from all publishers

Emerging work in vascular cognitive impairment (VCI) has begun to explore sGC modulators beyond systemic circulation. In preclinical VCI models, both stimulators and activators restore cerebral blood flow, reduce oxidative stress and attenuate endothelial and blood–brain barrier damage, suggesting a dual action on vascular and neural compartments. Complementary studies have identified cellular factors—such as thiols, small endogenous ligands and chaperone proteins—that modulate sGC sensitivity to NO and pharmacological agonists, revealing new strategies to enhance drug efficacy. Finally, mechanistic analysis of novel activators has uncovered a histidine-dependent mode of action: compounds like runcaciguat require a conserved histidine in the β1 subunit for activation of heme-free sGC, whereas earlier generation activators act independently of this residue. This classification informs future design of precision agonists for distinct oxidative states of the enzyme.

Soluble Guanylate Cyclase Modulators in Vascular Function publication trend

The graph below shows the total number of articles in soluble guanylate cyclase modulators in vascular function across all publications each year (not limited to Nature Index journals).

Technical terms

Soluble guanylate cyclase (sGC): A haem-containing enzyme that responds to NO by synthesising cGMP, a second messenger for vascular relaxation and homeostasis.

cGMP: Cyclic guanosine monophosphate, a signalling molecule that mediates vasodilation, inhibits smooth muscle proliferation and modulates platelet function.

sGC stimulator: A small molecule that binds to ferrous sGC and enhances its activity in synergy with NO.

sGC activator: A compound that directly activates oxidised or haem-free sGC independent of NO.

Heme oxidation/apo-sGC: Oxidative loss of the ferrous heme group in sGC, rendering it unresponsive to NO and necessitating activator drugs.

References

1. Soluble guanylyl cyclase: A novel target for the treatment of vascular cognitive impairment?. Pharmacological Research (2023).
2. Cellular Factors That Shape the Activity or Function of Nitric Oxide-Stimulated Soluble Guanylyl Cyclase. Cells (2023).
3. Runcaciguat activates soluble guanylyl cyclase via the histidine essential for heme binding and nitric oxide activation. Biochemical Pharmacology (2025).
4. Soluble GC stimulators and activators: Past, present and future. British Journal of Pharmacology (2021).
5. Pharmacological Characterization of IW-1973, a Novel Soluble Guanylate Cyclase Stimulator with Extensive Tissue Distribution, Antihypertensive, Anti-Inflammatory, and Antifibrotic Effects in Preclinical Models of Disease. Journal of Pharmacology and Experimental Therapeutics (2018).
6. Cardiovascular and pharmacological implications of haem-deficient NO-unresponsive soluble guanylate cyclase knock-in mice. Nature Communications (2015).