Endothelial cell (EC) Ca ²⁺ -activated K channels (SK _Ca and IK _Ca channels) generate hyperpolarization that passes to the adjacent smooth muscle cells causing vasodilation. IK _Ca channels focused within EC projections toward the smooth muscle cells are activated by spontaneous Ca ²⁺ events (Ca ²⁺ puffs/pulsars). We now show that transient receptor potential, vanilloid 4 channels (TRPV4 channels) also cluster within this microdomain and are selectively activated at low intravascular pressure. In arterioles pressurized to 80 mmHg, ECs generated low-frequency (∼2 min ⁻¹ ) inositol 1,4,5-trisphosphate receptor-based Ca ²⁺ events. Decreasing intraluminal pressure below 50 mmHg increased the frequency of EC Ca ²⁺ events twofold to threefold, an effect blocked with the TRPV4 antagonist RN1734. These discrete events represent both TRPV4-sparklet- and nonsparklet-evoked Ca ²⁺ increases, which on occasion led to intracellular Ca ²⁺ waves. The concurrent vasodilation associated with increases in Ca ²⁺ event frequency was inhibited, and basal myogenic tone was increased, by either RN1734 or TRAM-34 (IK _Ca channel blocker), but not by apamin (SK _Ca channel blocker). These data show that intraluminal pressure influences an endothelial microdomain inversely to alter Ca ²⁺ event frequency; at low pressures the consequence is activation of EC IK _Ca channels and vasodilation, reducing the myogenic tone that underpins tissue blood-flow autoregulation.

Discovered almost 40 years ago, the potent vasoconstrictor peptide endothelin-1 (ET-1) has a wide range of roles both physiologically and pathologically. In recent years, there has been a focus on the contribution of ET-1 to disease. This has led to the development of various ET receptor antagonists, some of which are approved for the treatment of pulmonary arterial hypertension, while clinical trials for other diseases have been numerous yet, for the most part, unsuccessful. However, given the vast physiological impact of ET-1, it is both surprising and disappointing that therapeutics targeting the ET-1 pathway remain limited. Strategies aimed at the pathways influencing the synthesis and release of ET-1 could provide new therapeutic avenues, yet research using cultured cells in vitro has had little follow up in intact ex vivo and in vivo preparations. This article summarises what is currently known about the synthesis, storage and release of ET-1 as well as the role of ET-1 in several diseases including cardiovascular diseases, COVID-19 and chronic pain. Unravelling the ET-1 pathway and identifying therapeutic targets has the potential to treat many diseases whether through disease prevention, slowing disease progression or reversing pathology.

Ca ²⁺ entry into vascular smooth muscle activates Ca ²⁺ signaling in the endothelium to protect tissue blood flow.

Increases in the diameter of small resistance arteries and arterioles occur secondary to processes that can be dependent or independent of changes in membrane potential. Hyperpolarization reduces the opening of voltage-gated calcium channels and thereby the stimulus for contraction of these resistance vessels. The stimulus for smooth muscle cell (SMC) hyperpolarization can occur directly via opening K+-channels expressed within those cells, but can also occur in response to stimulation of endothelial cells (ECs). This endothelium-dependent hyperpolarization (EDH) of smooth muscle often occurs in response to agonists that stimulate a rise in the Ca2+ concentration of ECs, which in turn can open Ca2+-activated K-channels to hyperpolarize the ECs, and if present, patent gap junctions connecting ECs to SMCs (myoendothelial gap junctions) can potentially enable direct electrical coupling. There is also evidence to suggest a diffusible factor or factors hyperpolarizes SMCs (EDHF pathways). Furthermore, whether evoked in ECs or SMCs, hyperpolarization can spread a considerable distance to neighboring cells via gap junctions, causing remote dilatation termed `spreading' or `conducted' dilatation. This process is endothelium-dependent and likely relies on both homo- and heterocellular gap junctions. This review will focus on the cross-talk between ECs and SMCs that coordinates the spread of hyperpolarization and thus modulates smooth muscle tone. (Circ J 2010; 74: 226-232)