Arterial blood pressure is controlled by vasodilatory factors such as nitric oxide (NO) that are released from the endothelium under the influence of fluid shear stress exerted by flowing blood Flow-induced endothelial release of ATP and subsequent activation of Gq/G11-coupled purinergic P2Y2 receptors have been shown to mediate fluid shear stress-induced stimulation of NO formation However, the mechanism by which fluid shear stress initiates these processes is unclear Here, we have shown that the endothelial mechanosensitive cation channel PIEZO1 is required for flow-induced ATP release and subsequent P2Y2/Gq/G11-mediated activation of downstream signaling that results in phosphorylation and activation of AKT and endothelial NOS We also demonstrated that PIEZO1-dependent ATP release is mediated in part by pannexin channels The PIEZO1 activator Yoda1 mimicked the effect of fluid shear stress on endothelial cells and induced vasorelaxation in a PIEZO1-dependent manner Furthermore, mice with induced endothelium-specific PIEZO1 deficiency lost the ability to induce NO formation and vasodilation in response to flow and consequently developed hypertension Together, our data demonstrate that PIEZO1 is required for the regulation of NO formation, vascular tone, and blood pressure

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Endothelial cation channel PIEZO1 controls blood pressure by mediating flow-induced ATP release

The mammalian genome encodes 28 distinct members of the transient receptor potential (TRP) superfamily of cation channels, which exhibit varying degrees of selectivity for different ionic species. Multiple TRP channels are present in all cells and are involved in diverse aspects of cellular function, including sensory perception and signal transduction. Notably, TRP channels are involved in regulating vascular function and pathophysiology, the focus of this review. TRP channels in vascular smooth muscle cells participate in regulating contractility and proliferation, whereas endothelial TRP channel activity is an important contributor to endothelium-dependent vasodilation, vascular wall permeability, and angiogenesis. TRP channels are also present in perivascular sensory neurons and astrocytic endfeet proximal to cerebral arterioles, where they participate in the regulation of vascular tone. Almost all of these functions are mediated by changes in global intracellular Ca2+ levels or subcellular Ca2+ signaling events. In addition to directly mediating Ca2+ entry, TRP channels influence intracellular Ca2+ dynamics through membrane depolarization associated with the influx of cations or through receptor- or store-operated mechanisms. Dysregulation of TRP channels is associated with vascular-related pathologies, including hypertension, neointimal injury, ischemia-reperfusion injury, pulmonary edema, and neurogenic inflammation. In this review, we briefly consider general aspects of TRP channel biology and provide an in-depth discussion of the functions of TRP channels in vascular smooth muscle cells, endothelial cells, and perivascular cells under normal and pathophysiological conditions.

Transient Receptor Potential Channels in the Vasculature

The existence of a mammalian family of TRPC ion channels, direct homologues of TRP, the visual transduction channel of flies, was discovered during 1995-1996 as a consequence of research into the mechanism by which the stimulation of the receptor-Gq-phospholipase Cbeta signaling pathway leads to sustained increases in intracellular calcium. Mammalian TRPs, TRPCs, turned out to be nonselective, calcium-permeable cation channels, which cause both a collapse of the cell's membrane potential and entry of calcium. The family comprises 7 members and is widely expressed. Many cells and tissues express between 3 and 4 of the 7 TRPCs. Despite their recent discovery, a wealth of information has accumulated, showing that TRPCs have widespread roles in almost all cells studied, including cells from excitable and nonexcitable tissues, such as the nervous and cardiovascular systems, the kidney and the liver, and cells from endothelia, epithelia, and the bone marrow compartment. Disruption of TRPC function is at the root of some familial diseases. More often, TRPCs are contributing risk factors in complex diseases. The present article reviews what has been uncovered about physiological roles of mammalian TRPC channels since the time of their discovery. This analysis reveals TRPCs as major and unsuspected gates of Ca(2+) entry that contribute, depending on context, to activation of transcription factors, apoptosis, vascular contractility, platelet activation, and cardiac hypertrophy, as well as to normal and abnormal cell proliferation. TRPCs emerge as targets for a thus far nonexistent field of pharmacological intervention that may ameliorate complex diseases.

Physiology and pathophysiology of canonical transient receptor potential channels

The endothelium, although only a single layer of cells lining the vascular and lymphatic systems, contributes in multiple ways to vascular homeostasis. Subsequent to the 1980 report by Robert Furch...

The endothelium: influencing vascular smooth muscle in many ways

Cellular interaction in blood vessels is maintained by multiple communication pathways, including gap junctions. They consist of intercellular channels ensuring direct interaction between endothelial and smooth muscle cells and the synchronization of their behavior along the vascular wall. Gap-junction channels arise from the docking of two hemichannels or connexons, formed by the assembly of six connexins, and achieve direct cellular communication by allowing the transport of small metabolites, second messengers, and ions between two adjacent cells. Physiologic variations in connexin expression are observed along the vascular tree, with most common connexins being Cx37, Cx40, and Cx43. Changes in the level of expression of connexins have been correlated to the development of vascular disease, such as hypertension, atherosclerosis, or restenosis. Recent studies on connexin-deficient mice highlighted key roles of these communication pathways in the development of these pathologies and confirmed the need for targeted pharmacologic approaches for their prevention and treatment. The aim of this issue is to review the current knowledge on the implication of gap junctions in vascular function and most common cardiovascular diseases.

Connexins in vascular physiology and pathology.

The effect of depleting intracellular Ca2+ stores on flow-induced vascular dilatation and the mechanism responsible for the vasodilatation were examined in rat isolated small mesenteric arteries.




The arteries were pressurized to 50 mmHg and preconstricted with phenylephrine. Intraluminal flow reversed the effect of phenylephrine, resulting in vasodilatation. Flow dilatation consisted of an initial transient peak followed by a sustained plateau phase. The magnitude of dilatation was markedly reduced by removing Ca2+ from the intraluminal flow medium.




Depletion of intracellular Ca2+ stores with either cyclopiazonic acid (CPA, 2 μM) or 1,4-dihydroxy-2,5-di-tert-butylbenzene (BHQ, 10 μM) significantly augmented the magnitude of flow dilatation. Flow-induced endothelial cell Ca2+ influx was also markedly enhanced in arteries pretreated with CPA or BHQ.




Flow-induced dilatation was insensitive to Nw-nitro-L-arginine methyl ester (100 μM) plus indomethacin (3 μM) or to oxyhemoglobin (3 μM), but was markedly reduced by 30 mM extracellular K+ or 2 mM tetrabutylammonium (TBA), suggesting an involvement of EDHF.




Catalase at 1200 U ml−1 abolished the flow-induced dilatation, while the application of exogenous H2O2 (90–220 μM) induced relaxation in phenylephrine-preconstricted arteries. Relaxation to exogenous H2O2 was blocked in the presence of 30 mM extracellular K+, and H2O2 (90 μM) hyperpolarized the smooth muscle cells, indicating that H2O2 can act as an EDHF.




In conclusion, flow-induced dilatation in rat mesenteric arteries can be markedly enhanced by prior depletion of intracellular Ca2+ stores. Furthermore, these data are consistent with a role for H2O2 as the vasodilator involved.






British Journal of Pharmacology (2006) 147, 506–515. doi:10.1038/sj.bjp.0706639

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Depletion of intracellular Ca2+ stores enhances flow-induced vascular dilatation in rat small mesenteric artery.

To test the possible involvement of TRPC3 in agonist-induced relaxation and flow-induced vasodilation in rat small mesenteric arteries. Male Sprague-Dawley rats were used in the present study. After 72 h-treatment of antisense oligo via tail vein injection, isometric tension and isobaric diameter measurement were carried out with isolated mesenteric artery segments by using either a Pressure Myograph or a Multi Myograph system. Endothelial [Ca2+]i changes were measured with a MetaFluor imaging system in response to flow or to 30 nmol/L bradykinin. Immunohistochemical study showed that the 72 h-treatment of antisense oligo via tail vein injection markedly decreased the TRPC3 expression in mesenteric arteries, indicating the effectiveness of the antisense oligo. Isometric tension and isobaric diameter measurement showed that, although the antisense oligo treatment did not affect histamine-, ATP-, and CPA-induced relaxation, it did reduce the magnitude of flow-induced vasodilation by approximately 13% and decreased bradykinin-induced vascular relaxation with its EC50 value raised by nearly 3-fold. Endothelial [Ca2+]i measurement revealed that treatment of the arteries with antisense oligos significantly attenuated the magnitude of endothelial [Ca2+]i rise in response to flow and to 30 nmol/L bradykinin. The results suggest that TRPC3 is involved in flow- and bradykinin-induced vasodilation in rat small mesenteric arteries probably by mediating the Ca2+ influx into endothelial cells.

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Ching-yuen Ngai

Papers

Depletion of intracellular Ca2+ stores enhances flow-induced vascular dilatation in rat small mesenteric artery.

TRPC3 is involved in flow- and bradykinin-induced vasodilation in rat small mesenteric arteries.