Activation of endothelial IK Ca channels underlies NO-dependent myoendothelial feedback

Kerr, Paul M.; Wei, Ran; Tam, Raymond; Sandow, Shaun L.; Murphy, Timothy V.; Ondrusova, Katarina; Lunn, Stephanie E.; Tran, Cam Ha T.; Welsh, Donald G.; Plane, Frances

doi:10.1016/j.vph.2015.09.001

Cited by 27 publications

(43 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Restriction of prostacyclin-dependent signaling is unlikely, because our indomethacin data suggest that PLA 2 -dependent mechanisms are upregulated following chronic hypoxia. However, chronic hypoxia may suppress the function of other NO synthase-independent pathways important to vasodilation not described in this report, including activation of stored forms of NO (16) and epoxyeicosatrienoic acids (14), as well as myoendothelial gap junctions (24,50). Resolution of which, if either, of these or other potential ionic or nonionic pathways are suppressed by chronic hypoxia requires additional studies.…”

Section: Discussionmentioning

confidence: 74%

Developmental acceleration of bradykinin-dependent relaxation by prenatal chronic hypoxia impedes normal development after birth

Blum-Johnston

Thorpe

Wee

et al. 2016

American Journal of Physiology-Lung Cellular and Molecular Phys

View full text Add to dashboard Cite

-Bradykinin-induced activation of the pulmonary endothelium triggers nitric oxide production and other signals that cause vasorelaxation, including stimulation of largeconductance Ca 2ϩ -activated K ϩ (BKCa) channels in myocytes that hyperpolarize the plasma membrane and decrease intracellular Ca 2ϩ . Intrauterine chronic hypoxia (CH) may reduce vasorelaxation in the fetal-to-newborn transition and contribute to pulmonary hypertension of the newborn. Thus we examined the effects of maturation and CH on the role of BKCa channels during bradykinin-induced vasorelaxation by examining endothelial Ca 2ϩ signals, wire myography, and Western immunoblots on pulmonary arteries isolated from near-term fetal (ϳ140 days gestation) and newborn, 10-to 20-day-old, sheep that lived in normoxia at 700 m or in CH at high altitude (3,801 m) for Ͼ100 days. CH enhanced bradykinin-induced relaxation of fetal vessels but decreased relaxation in newborns. Endothelial Ca 2ϩ responses decreased with maturation but increased with CH. Bradykinin-dependent relaxation was sensitive to 100 M nitro-L-arginine methyl ester or 10 M 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, supporting roles for endothelial nitric oxide synthase and soluble guanylate cyclase activation. Indomethacin blocked relaxation in CH vessels, suggesting upregulation of PLA2 pathways. BKCa channel inhibition with 1 mM tetraethylammonium reduced bradykinin-induced vasorelaxation in the normoxic newborn and fetal CH vessels. Maturation reduced whole cell BKCa channel ␣1-subunit expression but increased ␤1-subunit expression. These results suggest that CH amplifies the contribution of BKCa channels to bradykinin-induced vasorelaxation in fetal sheep but stunts further development of this vasodilatory pathway in newborns. This involves complex changes in multiple components of the bradykinin-signaling axes. potassium channels; sheep; pulmonary artery; contractility; maturation; hypoxia REGULATION OF SMOOTH MUSCLE tone in pulmonary arteries during development is a delicate balance of vasoconstrictive and vasorelaxant pathways. Endothelial cells play a crucial role in determining the overall level of vasorelaxation (39, 67), and endothelium-dependent relaxation is partially mediated through bradykinin stimulation (31). Bradykinin is a potent vasodilator that is important in the fetal pulmonary circulation, as well as during inflammation, and its relationship to pulmonary hypertension has been explored (5, 31, 83).Endothelial bradykinin receptor activation induces vasorelaxation through modulation of several different intracellular signaling pathways that are largely dependent on a rise of endothelial intracellular Ca 2ϩ ([Ca 2ϩ ] i ) (67). The most widely studied pathway is bradykinin-induced activation of endothelial nitric oxide (NO) synthase (eNOS), an enzyme that generates NO (64). NO acts on nearby smooth muscle cells to cause downstream stimulation of soluble guanylate cyclase (sGC) pathways that leads to vasorelaxation (3,45). Previous studies have shown that regulatio...

show abstract

Section: Discussionmentioning

confidence: 74%

Developmental acceleration of bradykinin-dependent relaxation by prenatal chronic hypoxia impedes normal development after birth

Blum-Johnston

Thorpe

Wee

et al. 2016

American Journal of Physiology-Lung Cellular and Molecular Phys

View full text Add to dashboard Cite

show abstract

“…In addition, with the exception of one study using endothelial tubes (68), all studies were performed using intact vessels that include SMCs that express voltage-gated ion channels (7, 31) and are coupled to ECs via myoendothelial junctions (25, 81, 83, 84). Thus, the presence of SMCs in intact vessels may indirectly affect EC V m and [Ca 2+ ] i .…”

Section: Introductionmentioning

confidence: 99%

Calcium and electrical signaling in arterial endothelial tubes: New insights into cellular physiology and cardiovascular function

Behringer

2017

Microcirculation

View full text Add to dashboard Cite

The integral role of the endothelium during the coordination of blood flow throughout vascular resistance networks has been recognized for several decades now. Early examination of the distinct anatomy and physiology of the endothelium as a signaling conduit along the vascular wall has prompted development and application of an intact endothelial “tube” study model isolated from rodent skeletal muscle resistance arteries. Vasodilatory signals such as increased endothelial cell (EC) Ca2+ ([Ca2+]i) and hyperpolarization take place in single ECs while shared between electrically coupled ECs through gap junctions up to distances of millimeters (≥ 2 mm). The small- and intermediate-conductance Ca2+ activated K+ (SKCa/IKCa or KCa2.3/KCa3.1) channels function at the interface of Ca2+ signaling and hyperpolarization; a bidirectional relationship whereby increases in [Ca2+]i activate SKCa/IKCa channels to produce hyperpolarization and vice versa. Further, the spatial domain of hyperpolarization among electrically coupled ECs can be finely tuned via incremental modulation of SKCa/IKCa channels to balance the strength of local and conducted electrical signals underlying vasomotor activity. Multifunctional properties of the voltage-insensitive SKCa/IKCa channels of resistance artery endothelium may be employed for therapy during the aging process and development of vascular disease.

show abstract

“…Furthermore, as tension develops, accumulated IP 3 can be transferred from the depolarized VSMCs to the overlying ECs via myoendothelial gap junctions. The result is S/IK Ca activation and hyperpolarization that serves to moderate myogenic or agonist-induced constriction (designated as “myoendothelial feedback”) [69, 70]. Thus, the level of K Ca activity induced following increased VSMC tone could limit further activation of these channels following EC stimulation, and thus their ability to participate in EDH.…”

Section: Introductionmentioning

confidence: 99%

Endothelium‐Derived Hyperpolarization and Coronary Vasodilation: Diverse and Integrated Roles of Epoxyeicosatrienoic Acids, Hydrogen Peroxide, and Gap Junctions

et al. 2016

Self Cite

View full text Add to dashboard Cite

Myocardial perfusion and coronary vascular resistance are regulated by signalling metabolites released from the local myocardium that act either directly on the vascular smooth muscle cells (VSMC) or indirectly via stimulation of the endothelium. A prominent mechanism of vasodilation is endothelium-derived hyperpolarization (EDH) of the arteriolar smooth muscle, with epoxyeicosatrienoic acids (EETs) and hydrogen peroxide (H2O2) playing important roles in EDH in the coronary microcirculation. In some cases, EETs and H2O2 are released as transferable hyperpolarizing factors (EDHFs) that act directly on the VSMCs. By contrast, EETs and H2O2 can also promote endothelial Ca2+-activated K+ channel activity secondary to the amplification of extracellular Ca2+ influx and Ca2+ mobilization from intracellular stores, respectively. The resulting endothelial hyperpolarization may subsequently conduct to the media via myoendothelial gap junctions, or potentially lead to the release of a chemically-distinct factor(s). Furthermore, in human isolated coronary arterioles dilator signalling involving EETs and H2O2 may be integrated; being either complimentary or inhibitory depending on the stimulus. With an emphasis on the human coronary microcirculation, this review addresses the diverse and integrated mechanisms by which EETs and H2O2 regulate vessel tone, and also examines the hypothesis that myoendothelial microdomain signalling facilitates EDH activity in the human heart.

show abstract

Activation of endothelial IK Ca channels underlies NO-dependent myoendothelial feedback

Cited by 27 publications

References 56 publications

Developmental acceleration of bradykinin-dependent relaxation by prenatal chronic hypoxia impedes normal development after birth

Developmental acceleration of bradykinin-dependent relaxation by prenatal chronic hypoxia impedes normal development after birth

Calcium and electrical signaling in arterial endothelial tubes: New insights into cellular physiology and cardiovascular function

Endothelium‐Derived Hyperpolarization and Coronary Vasodilation: Diverse and Integrated Roles of Epoxyeicosatrienoic Acids, Hydrogen Peroxide, and Gap Junctions

Contact Info

Product

Resources

About