Cardiovascular System

Smooth Muscle P2X Receptors

P2X receptors are ligand-gated ion channels that respond to extracellular adenosine triphosphate (ATP) released during cellular stress or injury. In vascular smooth muscle cells, activation of P2X receptors leads to calcium influx, resulting in vasoconstriction. P2X receptors contribute to the regulation of vascular tone and blood pressure in response to changes in ATP levels.

Transient Receptor Potential (TRP) Channels

Transient receptor potential subfamily V member 1 (TRPV1) channels are widely expressed in sensory nerves and play a role in pain perception. However, they are also present in the vascular system.  TRPV1 channels may be involved in regulating vascular tone and blood flow, particularly in response to certain inflammatory mediators. Transient receptor potential channels (TRPCs) are a subgroup of TRP channels involved in calcium signaling and regulation of smooth muscle contraction. Endothelial TRPV4 channels are a subtype of TRP channels primarily expressed in endothelial cells lining blood vessels. Activation of endothelial TRPV4 channels by various ligands, such as mechanical stress, shear stress, and certain chemical signals, leads to calcium influx and subsequent endothelial-dependent vasodilation. In addition, TRPV4 channels are involved in regulating vascular tone and blood flow in response to different physiological and pathological conditions.

Piezo Channels

Piezo channels are a family of mechanosensitive ion channels that have been identified in recent years. Piezo1 and Piezo2 are the two main subtypes expressed in blood vessels. Piezo1 channels are primarily found in endothelial cells, while Piezo2 channels are found in smooth muscle cells. Activation of Piezo channels in response to mechanical forces, such as shear stress, leads to calcium influx, resulting in various cellular responses, including vasodilation and modulation of vascular tone.

Stretch-Activated Ion Channels

Stretch-activated ion channels (SACs) are another group of mechanosensitive ion channels found in blood vessels. SACs respond to mechanical stretching or deformation of the cell membrane, such as that caused by changes in vessel diameter or blood pressure. Activation of SACs leads mainly  to calcium influx, which in turn triggers cellular signaling pathways involved in vascular physiology and pathophysiology.

Representative Channels:

• TRPV4

• TRPV1

• TRPC

• Piezo 1 & 2

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Sodium Channels

Sodium channels allow the influx of sodium ions into cardiac and vascular smooth muscle cells. The rapid influx of sodium ions into cardiac muscle initiates the depolarization phase of an action potential. In the vasculature, sodium ion influx helps to regulate vascular tone. Mutations in the genes that encode for sodium channel subunits are associated with congenital or acquired disorders, such as long QT syndrome type 3 (LQT3), Brugada syndrome (BrS), sick sinus syndrome (SSS), atrial fibrillation (A-fib), and dilated cardiomyopathy (DCM). Furthermore, vascular sodium channel dysfunction contributes to hypertension and peripheral artery disease (PAD).

Potassium Channels

Potassium channels enable the efflux of potassium ions out of cardiac cells, leading to membrane repolarization. In the vasculature, potassium channels contribute to membrane potential regulation and vaso/veno relaxation. Potassium channels can be classified into families based on their structure, function, and pharmacology. Important families found in the heart include inward rectifier potassium channels (Kir), voltage-gated potassium channels (Kv), calcium-activated potassium channels (KCa), and two-pore domain potassium channels (K2P). Mutations or dysregulation of these channels can cause various arrhythmias, including short QT syndrome (SQTS), long QT syndromes (type 1 & 2), and Andersen-Tawil syndrome (ATS). Dysfunctional potassium channels in the vasculature can lead to increased vascular tone and subsequent hypertension as well as other vasoconstriction-related diseases.

Calcium Channels

Calcium channels allow the influx of calcium ions into cardiac cells and smooth muscle cells of the vasculature. In the heart, calcium ion influx triggers the release of additional calcium from the sarcoplasmic reticulum, initiating myocardial contraction and regulating contractility. Calcium channels are also involved in regulating the pacemaker activity and excitability of cardiac cells. Calcium channels are composed of a pore-forming alpha1 subunit and several auxiliary subunits that modulate channel activity. The main types of calcium channels in the heart are L-type calcium channels (LTCC), T-type calcium channels (TTCC), and ryanodine receptors (RyR). Mutations or dysregulation of these channels can cause various cardiac diseases, such as long QT syndrome type 4 (LQT4), Timothy syndrome (TS), hypertrophic cardiomyopathy (HCM), DCM, CPVT, and heart failure. Dysfunction in vascular calcium channels contributes to conditions such as hypertension and peripheral artery disease.

Chloride Channels

Chloride ions enter cardiac cells and cells of the vasculature via chloride ion channels where they modulate the membrane potential in the heart and influence the activity of other ion channels in the heart and vasculature. Additionally, chloride ions are involved in regulating cell volume in vascular smooth muscle. Although less well studied than other ion channels in the heart, some evidence suggests that chloride channels may play a role in regulating cardiac rhythm, contractility, and response to ischemia-reperfusion injury. Major chloride channels in the heart include cystic fibrosis transmembrane conductance regulator (CFTR), chloride intracellular channel (CLIC), and volume-regulated anion channel (VRAC). Dysregulation or mutations of these chloride channels can contribute to various conditions, such as cystic fibrosis-related cardiomyopathy and atrial fibrillation. Furthermore, chloride channel dysfunction in the vasculature can lead to pathological alterations in cell volume and vasoconstriction.

Representative Channels:

• Nav1.5, 1.2 & 1.3, 1.7, & 1.9

• Kv1.2, Kv 1.5, Kv 1.6

• Kv11.1 (HERG)

• Kv4.2/4.3

• Kv7.1 (KVLQT1)

• Cav1.2 & 1.3

• Cav 3.1 & 3.2

• HCN2/4

Resources

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