Introduction

Second messengers are small, nonprotein intracellular molecules that amplify signals generated by cell-surface receptors. One such messenger, 3′,5′-cyclic guanosine monophosphate (cGMP), plays a central role in transducing extracellular signals into diverse physiological responses. Intracellular cGMP levels are tightly regulated by the opposing actions of guanylate cyclases, which synthesize cGMP from guanosine-5′-triphosphate, and phosphodiesterases (PDEs), which hydrolyze cGMP to inactive 5′-GMP and terminate signaling. Elevated cGMP activates protein kinase G and downstream effectors, thereby driving key physiological processes, including vasodilation.

cGMP signaling is essential for a broad range of functions, including synaptic transmission in vision, vascular homeostasis, and smooth muscle relaxation. Pharmacological targeting of the cGMP pathway has produced several successful therapies. Sildenafil (Viagra) enhances cGMP signaling by inhibiting cGMP-specific PDEs. More broadly, modulation of cGMP signaling underlies approved treatments for erectile dysfunction, pulmonary hypertension, heart failure, irritable bowel syndrome, coronary artery disease, and achondroplasia, highlighting the translational significance of this pathway.[1][2]

Fundamentals

Guanylate cyclases are lyase enzymes that catalyze the conversion of GTP into the second messenger cGMP.[3] cGMP signaling is tightly regulated within cells and mediates essential physiological processes, including vascular tone, sensory transduction, and cellular differentiation. Intracellular cGMP concentrations are precisely controlled by the opposing activities of guanylate cyclases, which synthesize cGMP, as well as PDEs, which degrade cGMP to inactive 5′-GMP. This equilibrium ensures that cGMP signaling responses are spatially and temporally restricted.

Guanylate Cyclases

Guanylate cyclases are classified into 2 major families based on structure, localization, and regulatory mechanisms. These families include soluble (sGCs) and particulate (pGCs) guanylate cyclases, the latter also termed "transmembrane guanylate cyclases". sGC is a cytosolic heterodimeric enzyme composed primarily of α1β1 (sGC1) or α2β1 (sGC2) subunits. This enzyme functions as the physiological receptor for nitric oxide. The binding of this gas to the heme moiety of the β subunit induces a conformational change that markedly increases catalytic activity, leading to rapid cGMP production. Signaling mediated by sGC is central to vasodilation, platelet inhibition, and neurotransmission.

pGCs are single-pass transmembrane receptors with an extracellular ligand-binding domain and an intracellular catalytic domain. Key cardiovascular members include guanylate cyclase A (GC-A, also known as natriuretic peptide receptor A) and guanylate cyclase B (GC-B, also known as natriuretic peptide receptor B), which function as homodimers and are activated by natriuretic peptides. GC-A responds primarily to atrial and brain natriuretic peptides, whereas GC-B is selectively activated by C-type natriuretic peptide. Activation of these receptors elevates intracellular cGMP levels and regulates blood pressure, cardiac remodeling, and fluid homeostasis. Additional pGC isoforms are expressed in sensory tissues and reproductive organs, where they control specialized cGMP-dependent processes.[4]

Phosphodiesterases

PDEs terminate cyclic nucleotide signaling by hydrolyzing cGMP or cyclic adenosine monophosphate (cAMP). To date, 11 PDE families (PDE1–PDE11) have been identified, each exhibiting distinct substrate specificity, regulatory mechanisms, and tissue distribution.[5] cGMP-specific PDEs, including PDE5, PDE6, and PDE9, selectively hydrolyze cGMP and contribute critically to vascular smooth muscle function, phototransduction in the retina, and neuronal signaling. Dual-specificity PDEs, including PDE1, PDE2, PDE3, PDE10, and PDE11, hydrolyze both cGMP and cAMP, facilitating cross-talk between cyclic nucleotide signaling pathways and enabling precise tuning of cellular responses. The coordinated regulation of cGMP synthesis by guanylate cyclases and degradation by PDEs ensures tightly controlled cGMP signaling. This regulation supports the diverse physiological and pathophysiological functions of cGMP.

Issues of Concern

Modulation of the cGMP signaling pathway offers substantial therapeutic potential but presents significant challenges and side effects that require careful consideration. cGMP regulates a wide range of physiological processes across multiple cell types, particularly within the cardiovascular system, and dysregulation at any level of the pathway can contribute to cardiovascular disease. Excessive activation of cGMP signaling has also been implicated in enterotoxigenic Escherichia coli infections, where elevated cGMP disrupts intestinal sodium and water absorption, resulting in secretory diarrhea.[6][7]

Off-target and systemic effects remain a major limitation of cGMP-based therapies. The widespread distribution of cGMP signaling enables pharmacological overstimulation of nontarget tissues. Common adverse effects include hypotension, dizziness, lightheadedness upon postural changes, blurred vision, confusion, sweating, fatigue, shortness of breath, and abnormal bleeding or bruising, reflecting excessive vasodilation and altered vascular homeostasis.

Visual disturbances are a well-recognized side effect of PDE5 inhibitors, resulting from partial inhibition of retinal PDE6, a critical enzyme in phototransduction. These effects highlight the challenge of achieving isoform- and tissue-specificity within the PDE family.[8][9] Use of nitric oxide donors presents an additional concern, as chronic exposure can induce nitrate tolerance. Under conditions of elevated reactive oxygen species, nitric oxide donors may promote the formation of reactive nitrogen species, thereby contributing to endothelial dysfunction rather than therapeutic benefit.[10]

Clinical development of sGC activators has encountered significant challenges. Early compounds, such as cinaciguat, were associated with a high risk of severe hypotension, limiting clinical utility and highlighting the narrow therapeutic window of potent cGMP activation. Drug–drug interactions further complicate cGMP-based therapies. Concomitant administration of PDE5 inhibitors and nitrates is contraindicated due to the risk of profound and potentially life-threatening hypotension, necessitating careful patient selection and monitoring.[11]

Targeting cGMP signaling in the central nervous system (CNS) has produced mixed results. Results from early clinical trials of PDE5 and PDE9 inhibitors failed to demonstrate efficacy, potentially reflecting low basal cGMP production in CNS disorders or compensation by other PDE isoforms. The development of CNS-penetrant sGC stimulators has renewed interest in this approach, with emerging evidence of early clinical benefit.

Cellular Level

The biological effects of cGMP are mediated primarily by cGMP-dependent protein kinase (abbreviated as "PKG" or "cGK"). PKGI, the predominant isoform in cardiovascular tissues, exists as 2 splice variants, PKGIα and PKGIβ, with PKGIα playing a key role in regulating vascular tone. cGMP signaling exhibits high compartmentalization within cells, enabling specificity of downstream responses. Distinct intracellular cGMP microdomains are shaped by localized PDE activity. In cardiac myocytes and adipocytes, cGMP generated by natriuretic peptide receptors and nitric oxide–activated soluble guanylate cyclase is differentially regulated by PDE1, PDE3, and PDE9. In infectious contexts, activation of guanylate cyclase C (GC-C) by bacterial heat-stable enterotoxins induces robust cGMP accumulation in intestinal epithelial cells and promotes cGMP secretion, modulating epithelial gene expression and cytokine signaling. Tissue-specific expression of PDEs further refines cGMP signaling, with PDE5 enriched in cardiovascular and pulmonary tissues and PDE10A predominantly expressed in the brain.[12]

In addition to kinase-mediated signaling, cyclic nucleotide–gated (CNG) ion channels serve as direct effectors of cyclic nucleotides. These nonselective cation channels mediate sodium and calcium influx and are best characterized in retinal photoreceptors, where rod and cone CNG channels are preferentially activated by cGMP. CNG channels are also expressed in olfactory sensory neurons and the pineal gland. Downstream of atrial natriuretic peptide, cGMP signaling contributes to vasodilation and reduced sodium reabsorption in renal collecting tubules, demonstrating the broad physiological relevance of cGMP signaling.[13][14]

Molecular Level

Intracellular cGMP levels are tightly regulated by the opposing actions of guanylate cyclases, which synthesize cGMP from guanosine triphosphate, and PDEs, which hydrolyze cGMP to inactive GMP, thereby terminating signaling. cGMP production occurs through 2 principal mechanisms. In the nitric oxide pathway, nitric oxide binds to sGC and markedly enhances the enzyme's catalytic activity, resulting in rapid cGMP generation. Alternatively, receptor-mediated cGMP synthesis occurs when natriuretic peptides bind to pGCs.[15] Notably, cGMP is the only second messenger whose synthesis is directly stimulated by a gaseous signaling molecule. 

cGMP mediates cellular effects through 3 major classes of effectors. The primary mediators are PKGs, serine-threonine kinases activated by cGMP binding. Two PKG subclasses have been identified, PKGI and PKGII, which differ in tissue distribution and substrate specificity. CGMP also regulates CNG ion channels, producing sodium and calcium influx in specialized cell types. In addition, cGMP can indirectly modulate protein kinase A signaling via cross-talk mediated by PDEs, rather than through strong direct activation, reflecting integration between cGMP and cAMP pathways.[16]

The 11 PDE families, PDE1 through PDE11, differ in substrate specificity, kinetics, and regulatory properties. PDE5, PDE6, and PDE9 selectively hydrolyze cGMP, whereas PDE1, PDE2, PDE3, PDE10, and PDE11 hydrolyze both cGMP and cAMP. This dual specificity allows cGMP to influence cAMP signaling. For example, cGMP binding to certain PDEs can inhibit cAMP hydrolysis, thereby elevating cAMP levels and downstream signaling.[17]

Results from recent studies have provided important insights into the regulation of guanylate cyclase and the complexity of cGMP signaling pathways. SGC functions as a heterodimeric enzyme in which nitric oxide binds to the ferrous (Fe2+) heme of the β1 subunit, disrupting the histidine–heme interaction and inducing conformational changes that activate the catalytic domain. Structural studies have further elucidated the mechanisms by which sGC stimulators and activators enhance enzymatic activity. PDEs have been shown to hydrolyze noncanonical cyclic nucleotides, such as cyclic CMP and cyclic UMP, which have recently been implicated in bacterial immune signaling. In addition, PKGI may be activated through redox-dependent mechanisms, including oxidation by hydrogen peroxide, revealing a cGMP-independent mode of PKG regulation with potential physiological relevance.

Function

Nitric oxide–dependent elevation of intracellular cGMP mediates a wide range of physiological effects, primarily through activation of PKGI. These effects include vascular and gastrointestinal smooth muscle relaxation, inhibition of platelet aggregation, cardioprotection—including protection against hypertrophy and ischemia–reperfusion injury—and contributions to cognitive function. Consistent with these roles, mice lacking PKGI exhibit impaired gut motility and elevated blood pressure, reflecting defective nitric oxide–cGMP signaling in smooth muscle. PKGI signaling also contributes to neuronal plasticity, erectile function, lower urinary tract function, and regulation of endothelial permeability. Additional PKG-mediated processes include reduction of intracellular calcium levels, regulation of bone metabolism, modulation of renal electrolyte handling, control of melanocyte responses to UV radiation, and feedback regulation of cGMP signaling through PDE activation.

CGMP exerts direct effects by binding to CNG ion channels, which require ligand binding for channel opening and maximal ion conductance. In photoreceptors and olfactory sensory neurons, cGMP-dependent CNG channel activation underlies signal amplification critical for visual and olfactory discrimination. CNG channels also contribute to calcium homeostasis: reduced intracellular calcium activates guanylate cyclase–activating proteins, thereby increasing cGMP synthesis and promoting calcium influx through CNG channels.

Hyperpolarization-activated cyclic nucleotide–gated (HCN) channels, a related channel family primarily regulated by cAMP but modulated by cGMP, are highly expressed in the heart and brain. These channels function as pacemakers, governing rhythmic cardiac and neuronal activity. The PDE superfamily is expressed heterogeneously across tissues and exhibits variable affinities for cGMP. This diversity enables precise spatial and temporal regulation of cGMP signaling throughout the body.

Mechanism

CGMP signaling is a clinically actionable pathway that regulates vascular, metabolic, and neurological functions through activation of PKGs and is tightly controlled by PDEs. In the vasculature, cGMP serves as a central mediator of smooth muscle relaxation and antithrombotic signaling, and its dysregulation contributes to hypertension, atherosclerosis, and inflammatory vascular disease. Context-dependent effects of cGMP on vascular cell proliferation, shaped by signaling source (eg, sGC versus pGC) and subcellular compartmentalization, underscore the need for pathway-selective therapeutic strategies. Natriuretic peptide–driven cGMP signaling suppresses immune cell activation, whereas nitric oxide–dependent cGMP signaling limits leukocyte recruitment and thrombosis, revealing anti-inflammatory mechanisms with potential application in cardiovascular disease.[18][19]

Beyond its role in vascular biology, cGMP is a promising target for the treatment of metabolic disorders. In adipose tissue, cGMP enhances mitochondrial biogenesis, increases energy expenditure, promotes browning of white fat, and improves insulin sensitivity, indicating therapeutic potential for obesity and type 2 diabetes. CGMP signaling also regulates hepatic inflammation, pancreatic hormone secretion, and hypothalamic control of appetite and fluid balance.[20]

Testing

Urinary cGMP has emerging potential as a noninvasive biomarker of renal function and injury. In clinical settings, iodine-based radiocontrast agents used for angiographic procedures carry a risk of contrast-induced nephropathy, particularly in patients with diabetes or preexisting kidney disease. Therefore, identification of biomarkers that predict renal vulnerability and adverse outcomes has become a priority. Renal function directly influences urinary cGMP excretion, and several studies have evaluated urinary cGMP levels as a prognostic indicator. A urine cGMP-to-creatinine ratio of at least 120 μmol/mmol prior to contrast exposure has been associated with an increased risk of dialysis requirement and all-cause mortality within 90 days in high-risk patient populations, supporting the potential utility of this ratio in clinical risk stratification.[21][22]

At the cellular level, phosphorylated vasodilator-stimulated phosphoprotein (P-VASP) serves as a well-established surrogate marker of physiological cGMP signaling, acting as a primary substrate of PKGs. Measurements of urinary cGMP and P-VASP provide complementary readouts of systemic and intracellular cGMP pathway activity. Tools such as SponGee, a genetically encoded chelator of cGMP, enable the precise manipulation of cGMP at subcellular and cell–type–specific levels, facilitating mechanistic studies that may inform the development of cGMP-based diagnostics and therapeutics for renal and cardiovascular disease.[23][24]

Pathophysiology

Dysregulation of cGMP signaling constitutes a central mechanism underlying many cardiovascular diseases and is increasingly described as a “cGMPopathy.” In the pulmonary vasculature, cGMP is essential for the relaxation of vascular smooth muscle. Activation of PKGI and PKGII lowers intracellular calcium by opening calcium-activated potassium channels, stimulating sarcoplasmic reticulum calcium-transporting adenosine triphosphatases, and inhibiting ρ kinase, thereby promoting vasodilation.[25]

Impairment of this pathway contributes directly to pulmonary hypertension, in which reduced nitric oxide bioavailability, oxidative inhibition of SGC, or enhanced PDE5-mediated cGMP degradation limit PKG activation and favor vasoconstriction. In heart failure, diminished cGMP signaling and resistance to natriuretic peptide pathways drive disease progression in heart failure with either preserved (HFpEF) or reduced ejection fraction. Reduced myocardial PKG activity is characteristic of HFpEF, whereas PDE9A, which regulates nitric oxide–independent cGMP pools, promotes pathological cardiac hypertrophy.[26] Genetic evidence further links impaired nitric oxide–cGMP signaling to atherosclerosis and myocardial infarction, with rare variants in nitric oxide–activated guanylate cyclase and PDE5 associated with increased risk of coronary artery disease. Collectively, these findings identify cGMP signaling as a key therapeutic target in cardiovascular disease.

Clinical Significance

Therapeutic targeting of the cGMP pathway primarily involves stimulating guanylate cyclases or inhibiting phosphodiesterases to increase intracellular cGMP in specific tissues. SGC stimulators are under clinical investigation for pulmonary hypertension, as they enhance cGMP synthesis independently of nitric oxide. PDE5 inhibitors, such as sildenafil, are widely used for erectile dysfunction and pulmonary arterial hypertension and are being explored for cardioprotective effects, with evidence that elevated myocardial cGMP improves pulmonary vascular tone and right ventricular function, including in diastolic heart failure.[27]

Modulation of cGMP signaling has also demonstrated benefit in visceral pain disorders. In irritable bowel syndrome with constipation, GC-C agonists reduce abdominal pain by decreasing nociceptor hypersensitivity and increasing extracellular cGMP within the intestinal epithelium.[28] In the kidney, PKGI activation via cGMP elevation is associated with renoprotective effects in preclinical and clinical studies, including reduced fibrosis, modulation of platelet aggregation, and improved vascular function. Excessive cGMP signaling can be deleterious in specific contexts. In retinal dystrophy models, elevated cGMP is linked to photoreceptor degeneration, potentially resulting from dysregulated calcium influx through CNG channels and PKGI overactivation.[29][30]

Several established cardiovascular drugs act through the cGMP pathway. Nitrates and nitroprusside increase nitric oxide–dependent cGMP signaling. Hydralazine indirectly enhances vasodilation in part via cGMP-dependent mechanisms, contributing to its efficacy in hypertension and heart failure.[31][32][33]

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Disclosure: Franklin Iheanacho declares no relevant financial relationships with ineligible companies.

Disclosure: Nader Rahimi declares no relevant financial relationships with ineligible companies.