Abstract
Significance: In this review, we discuss the role of nitric oxide (NO) as a key physiological mechanotransducer modulating both local and systemic heterocellular communication and contributing to the integrated (patho)physiology of the cardiovascular system. A deeper understanding of mechanotransduction-mediated local and systemic nodes controlling heterocellular communication between the endothelium, blood cells, and other cell types (e.g., cardiomyocytes) may suggest novel therapeutic strategies for endothelial dysfunction and cardiovascular disease.Recent Advances: Mechanical forces acting on mechanoreceptors on endothelial cells activate the endothelial NO synthase (eNOS) to produce NO. NO participates in (i) abluminal heterocellular communication, inducing vasorelaxation, and thereby regulating vascular tone and blood pressure; (ii) luminal heterocellular communication, inhibiting platelet aggregation, and controlling hemostasis; and (iii) systemic heterocellular communication, contributing to adaptive physiological processes in response to exercise and remote ischemic preconditioning. Interestingly, shear-induced eNOS-dependent activation of vascular heterocellular communication constitutes the molecular basis of all methods applied in the clinical routine for evaluation of endothelial function.Critical Issues and Future Directions: The integrated physiology of heterocellular communication is still not fully understood. Dedicated experimental models are needed to analyze messengers and mechanisms underpinning heterocellular communication in response to physical forces in the cardiovascular system (and elsewhere). Antioxid. Redox Signal. 26, 917–935.
Highlights
Nitric oxide (NO) is one of the evolutionary, oldest [46], and best characterized messengers, playing a key role in local and systemic heterocellular communication
nitric oxide (NO) has a high affinity for Fe2+-heme centers and rapidly reacts with the soluble guanylate cyclase; sGC catalyzes the conversion of guanosine-5¢triphosphate (GTP) into the second messenger 3¢,5¢-cyclic guanosine monophosphate, which in turn activates its downstream signaling cascade [8, 32]
We focus on the mechanosensors, which are likely responsible for endothelial NO synthase (eNOS) activation in the endothelium mainly by two mechanisms (i) increases in [Ca+2]i or (ii) activation of phosphorylation cascades leading to regulation of eNOS activity
Summary
Nitric oxide (NO) is one of the evolutionary, oldest [46], and best characterized messengers, playing a key role in local and systemic heterocellular communication. NO carries physicochemical characteristics, making it an ideal messenger for transferring physiological signals within cells, through cells, and among tissues. Free radicals participating in redox signaling, for example, superoxide radical anion (O2-), NO is more stable and less reactive toward biologically relevant thiols,a such as cysteine and glutathione [53], which are found in millimolar concentrations in cells and tissues. NO has a high affinity for Fe2+-heme centers and rapidly reacts with the soluble guanylate cyclase (sGC; EC 4.6.1.2); sGC catalyzes the conversion of guanosine-5¢triphosphate (GTP) into the second messenger 3¢,5¢-cyclic guanosine monophosphate (cGMP), which in turn activates its downstream signaling cascade [8, 32]. NO may exert pleiotropic cGMP-independent effects via S-nitrosation of key cysteines in enzymes and proteins modifying their activity [6]
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