Communication Is Key: Mechanisms of Intercellular Signaling in Vasodilation

Abstract

Thirty years ago Robert F. Furchgott concluded that nitric oxide, a compound traditionally known to be a toxic component of fuel exhaust, is in fact released from the endothelium, and in a paracrine fashion, induces relaxation of underlying vascular smooth muscle resulting in vasodilation. This discovery has helped pave the way for a more thorough understanding of vascular inter- and intracellular communication that supports the process of regulating regional perfusion to match local tissue oxygen demand. Vasoregulation is not only controlled by endothelial release of a diverse class of vasoactive compounds such as nitric oxide, arachidonic acid metabolites, and reactive oxygen species, but also via physical forces on the vascular wall and through electrotonic conduction through gap junctions. Although the endothelium is a critical source of vasoactive compounds, paracrine mediators can also be released from surrounding parenchyma such as perivascular fat, myocardium, and cells in the arterial adventitia to exert either local or remote vasomotor effects. The focus of this review will highlight the various means by which intercellular communication contributes to mechanisms of vasodilation. Paracrine signaling and parenchymal influences will be reviewed as well as regional vessel communication via gap junctions, connexons, and myoendothelial feedback. More recent modes of communication such as vesicular and microRNA signaling will also be discussed.

Endothelium-Derived Hyperpolarizing Factor and Myoendothelial Coupling: The in vivo Perspective

“…This feedback is tightly controlled ( Straub et al, 2012 ; Biwer et al, 2018 ) and, interestingly, the artificial modulation of heterocellular contact in larger arteries may alter their vascular function ( Shu et al, 2019 ). The hypothesis that myoendothelial junctions serve as conduits for charge transfer and represent mechanistically the EDH-type dilation instead of an EDHF that traverses the extracellular space has been reviewed excellently in more detail elsewhere ( Griffith, 2004 ; Figueroa and Duling, 2009 ; de Wit and Griffith, 2010 ; Garland et al, 2011 ; Ellinsworth et al, 2014 ; Freed and Gutterman, 2017 ; Garland and Dora, 2017 ).…”

“…The outstanding molecules acting as chemical mediators in this pathway of intercellular communication are PG [cyclooxygenase (COX) products] and the gaseous transmitter nitric oxide (NO) which is produced by endothelial NO-synthase and easily diffuses through plasma membranes to reach its target, the intracellularly localized soluble guanylyl cyclase (sGC; Qian and Fulton, 2013 ; Luo et al, 2016 ; Nava and Llorens, 2019 ). Apart from these molecules, other chemical entities have been suggested to be released from ECs and relax smooth muscle, among them K + ions, lipophilic compounds (e.g., epoxyeicosanoids, EETs), proteins (C-type natriuretic peptide), radicals [hydrogen peroxide (H 2 O 2 )], and other gaseous molecules [CO, hydrogen sulfide (H 2 S); Figure 1 ; Feletou and Vanhoutte, 2009 ; Garland et al, 2011 ; Feletou et al, 2012 ; Ellinsworth et al, 2014 , 2016 ; Feletou, 2016 ; Freed and Gutterman, 2017 ; Garland and Dora, 2017 ].…”

“…However, this view was challenged and a direct electrotonic way of communication was suggested. Charge is transferred from ECs to smooth muscle through intercellular channels [myoendothelial gap junctions (GJs), MEGJs] driven by an initial endothelial hyperpolarization that spreads radially into the vessel wall ( Figure 1 ; de Wit and Griffith, 2010 ; Freed and Gutterman, 2017 ; Garland and Dora, 2017 ).…”

You Are Only as Frail as Your Arteries: Prehabilitation of Elderly Surgical Patients

“…Increased intraluminal pressure within the microcirculation will also impair autoregulatory processes and therefore may prove to be detrimental to cerebral, coronary, and renal perfusion [26,27]. Likewise, the endothelium within resistance vessels plays a critical role maintaining vascular homeostasis by generating and releasing various mediators that act in an autocrine or paracrine fashion to other surrounding tissues [28,29]. The numerous endothelial-derived compounds produced to control vascular tone and maintain balance between anti-inflammatory and proinflammatory pathways will not be discussed in this review; however, it should be noted that the predominant mediator produced in healthy adult humans is nitric oxide (NO) and loss of the ability to vasodilate to this compound is referred to as endothelial dysfunction.…”

Echinacoside‑induced nitric oxide production in endothelial�cells: Roles of androgen receptor and the PI3K‑Akt pathway

“…being NO, formed from the endothelial isoform of eNOS, which results in phosphorylation(19). Under normal conditions, eNOS remains inactive when bound to caveolin, and is activated with the following succession of events in endothelial cells: i) eNOS dissociates from caveolin-1 and associates with ca 2+ /caM; ii) heat shock protein (HSP)90 promotes eNOS…”