This issue of The Journal of Pharmacology and Experimental Therapeutics contains a comprehensive paper evaluating a novel therapy for coronary vasomotor disorders (Tawa et al., 2024). There is a desperate need to develop new therapies for these diagnostically elusive disorders that are often difficult to treat. Basic science studies play a fundamental role in identifying these therapies but are challenging to translate into a clinical context. This editorial provides the clinical context for the coronary vasomotor disorders and the challenges in translating basic science findings.

Obstructive atherosclerotic coronary artery disease (CAD) is readily diagnosed by coronary artery imaging (coronary angiography), thereby accounting for the ischemic chest pain experienced by these patients and guiding the use of well-established medical therapies and/or revascularization therapies (i.e., coronary stenting or coronary artery bypass grafting). However, as many as half of the patients undergoing elective coronary angiography for ischemic chest pain do not have obstructive CAD to account for their symptoms. These patients are diagnosed with the syndrome of ischemia with nonobstructive coronary arteries (INOCA) (Beltrame et al., 2021). Potential ischemic mechanisms responsible for the symptoms in INOCA include coronary artery spasm and/or coronary microvascular dysfunction, which are usually not seen on routine diagnostic coronary angiography because of their dynamic nature and the inability to clinically image the microvasculature. The corresponding clinical disorders to these pathophysiological entities are vasospastic angina (Beltrame et al., 2017) (i.e., large vessel coronary artery spasm) and microvascular angina (Ong et al., 2018) (i.e., coronary microvascular dysfunction), with the overall term for these entities being coronary vasomotor disorders, reflecting their abnormal vasomotor responses.

Although the diagnosis of coronary vasomotor disorders is challenging, specialized diagnostic testing (functional coronary angiography) is being increasingly used thereby enabling the diagnosis of these patients (Beltrame et al., 2022). However, the therapies available for these patients remain limited since revascularization therapies are not an option and the standard anti-ischemic medications have been primarily designed for patients with obstructive CAD. Thus, there is a need to develop novel therapies targeting these coronary vasomotor disorders. Considering that the vascular smooth muscle cell (VSMC) contractile state is the primary determinant of vasomotor tone, understanding the underlying molecular mechanisms responsible for the contraction-relaxation of these cells is key to identifying new therapeutic targets.

VSMC contraction involves actin-myosin coupling in response to myosin phosphorylation, with 1) the phosphorylation regulated by calcium-calmodulin–myosin light chain kinase interaction and 2) dephosphorylation by the myosin light chain phosphatase (MLCP)–MYPT subunit interaction (see Fig. 1). In turn, these are respectively regulated by the VSMC cytosolic calcium status and the Rho kinase/protein kinase-G (PKG) pathways (see Fig. 1). The endothelium exerts its effect on the VSMC by releasing nitric oxide, which stimulates VSMC cyclic guanylyl monophosphate production via soluble guanylate cyclase (sGC) and in turn activates PKG, which phosphorylates large conductance voltage and calcium-activated potassium channels. Increasing potassium efflux causes membrane hyperpolarization and in turn limits activation of extracellular calcium entry via voltage-gated L-channels, limiting vasoconstriction (see Fig. 1). More recent data suggest an additional role of PKG on the activity state of MLCP, specifically PKG-dependent phosphorylation of MYPT at Serine 854 adjacent to the inhibitory phosphothreonine 855 Rho kinase site (Sutherland et al., 2016). It is therefore conceivable that sGC activation could also lead to Serine 854 phosphorylation and prevent Rho kinase-mediated inhibition of MLCP, thus limiting calcium sensitization and providing a secondary mechanism for vasodilatation. Considering these molecular mechanisms, basic research studies are required to screen for potential therapeutic agents in the treatment of coronary vasomotor disorders.

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Fig. 1.

Molecular mechanisms of vascular smooth muscle cell contraction/relaxation with reference to a soluble guanylate cyclase activator. Direct activation of sGC activates PKG that leads to phosphorylation of large conductance voltage and BK_Ca channels, potassium efflux, membrane hyperpolarization, and less calcium entry through Ca_V1.2, favoring vasodilation. PKG-dependent phosphorylation of Ser 854 MYPT, the myosin targeting subunit of myosin phosphatase, “activates” MLCP favoring vasodilation, preventing ROK-mediated inhibition by Thr855 phosphorylation of the MYPT targeting subunit of myosin phosphatase (Grassie et al., 2012). Notionally the serine phosphorylation limits an inhibitory conformation change mediated by Rho kinase-dependent phosphorylation of Thr855 favoring activation of myosin phosphatase, less myosin phosphorylation, and more vasodilation. In the absence of PKG-mediated phosphorylation of Ser 854 MYPT, Rho kinase-dependent phosphorylation of Thr855 MYPT inhibits myosin phosphatase favoring more myosin light chain phosphorylation and vasoconstriction (Grassie et al., 2012). BAY 60-2770, a direct activator of sGC; BK⁺ _Ca, large conductance calcium-activated potassium channel; CaM, calmodulin; cGMP, cyclic guanylate monophosphate; GPCR, G-protein coupled receptor; L-channel Ca_V1.2, large conductance voltage gated calcium channel; MLCK, myosin light chain kinase; MLCP, myosin light chain phosphatase; MYPT, the regulator and targeting subunit of myosin phosphatase; NO, nitric oxide; PKG, protein kinase G; ROK, Rho kinase; sGC, soluble guanylyl cyclase.

In this issue, Tawa et al. (2024), evaluate a new potential therapeutic agent for coronary vasomotor disorders, assessing the coronary vasomotor properties of a sGC activator (BAY 60-2770) via three experimental models. Using a canine-isolated coronary artery model, pretreatment with the sGC activator suppressed constrictor-induced contraction responses both to receptor-mediated (i.e., prostaglandin F2alpha, endothelin-1, and serotonin) and depolarization-mediated (high potassium solution) stimuli. Clinically, this suggests that vasoconstrictor responses mediated by these physiologic stimuli can be modulated by preventative therapy with an sGC activator. Using porcine-isolated coronary vessels, the investigators demonstrated 1) 3,4-diaminopyridine-induced phasic contractions could be suppressed by the sGC activator and 2) segmental heterogeneity in sGC activator effects, with a “small” coronary artery (diagonal) segment showed greater inhibition to induced contractions than the large coronary artery (left anterior descending artery) segment. The clinical implications of these findings are the potential for an sGC activator to inhibit coronary spasm and that the inhibitory effects are greater in the smaller vessels. Finally, utilizing a rat vasopressin-induced myocardial ischemia model, pretreatment with the sGC activator inhibited the ischemic electrocardiogram changes. This is consistent with the sGC activator having anti-ischemic properties in a vasoconstrictor-induced ischemic model. Accordingly, these experiments provide mechanistic insights at an in vivo level for the potential benefits of sGC activators in coronary vasomotor disorders.

The investigators have gone to great lengths with these three models to mimic the clinical scenario and provide important background for clinical studies. However, there are several limitations in translating these findings to the clinical scenario. As with all animal studies, translation to human physiology is difficult, and there are well-documented species differences in vascular physiology. Furthermore, in vitro models provide important insights into the direct vascular effects of therapeutic agents but remove any regulatory homeostatic mechanism that may counteract the effects. Besides these common design issues with basic research studies, the vascular studies have more specific issues as outlined next.

First, the investigators report segmental heterogeneity in vascular responses between large (left anterior descending) and small (diagonal) coronary arteries. Although important and intriguing, the diagonal coronary artery is an epicardial coronary artery and may not behave as the true microvessels (i.e., prearterioles and arterioles). The in vivo model may reflect both large and microvessel vascular function, but the vasopressin stimulus is not a true physiologic stimulus, although the agent is occasionally used in an intensive care setting for circulatory support. Thus, more work is needed to identify the impact of these agents in the coronary microvasculature.

Second, coronary artery spasm in humans is not a progressive constrictor anomaly to increasing levels of local/circulating vasoconstrictors but a sudden-onset profound constrictor response (i.e., >90% by clinical definitions) in vessels that are hypersensitive to standard stimuli. For example, provocative spasm testing with intracoronary acetylcholine typically produces mild constriction (10%–30%) or even vasodilation in healthy controls, but the same dose will produce profound >90% spasm in patients with vasospastic angina. A coronary spasm model that mimics vasospastic angina is an in vivo porcine model where adventitial interleukin 1β application produces localized inflammation and a mild nonobstructive stenotic lesion, which develops angiogram-documented coronary artery spasm with the administration of intracoronary serotonin (Shimokawa, 2014). This model and its derivatives utilizing endothelial denudation demonstrate the three key pathophysiological mechanisms contributing to coronary artery spasm, namely endothelial dysfunction, vascular smooth muscle hyperreactivity, and adventitial inflammation. This elaborate in vivo model is ideal for future therapeutic drug testing.

Third, in coronary microvascular disorders, several pathophysiological mechanisms appear to contribute. Some of these patients have an increased resting coronary microvascular resistance with the capacity to vasodilate to hyperemic stimuli (e.g., exercise or adenosine), while others have a normal resting coronary microvascular resistance but do not appropriately vasodilate to hyperemic stimuli. In others, the blood flow may be normal at rest and respond appropriately to hyperemic stimuli but develop microvascular spasm with certain provocative stimuli. This spectrum of coronary microvascular dysfunction is difficult to replicate in any one laboratory-based model and requires ongoing clinical and laboratory-based mechanistic studies.

Although there are limitations in translating basic laboratory findings into clinical practice, it is imperative that more basic discovery research is undertaken to identify novel agents that may be effective in coronary vasomotor disorders. These may include variations in available molecules that are more effective in either inhibiting established vasoconstrictor pathways or enhancing vasodilatory pathways. Alternatively, identifying novel pathways that influence coronary vasomotor tone and thus new therapeutic targets for treating these disabling conditions is important. Certainly, there is a large cohort of frustrated patients (and clinicians) who are seeking new therapies to treat these disorders. As shown by Tawa et al. (2024), in this issue, the basic laboratory provides an opportunity to screen novel molecules as a prelude to clinical studies in patients with coronary vasomotor disorders. Moreover, identification of novel vasodilatory agents may have implications for other cardiovascular disorders.

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