Modulation of Local and Systemic Heterocellular Communication by Mechanical Forces: A Role of Endothelial Nitric Oxide Synthase

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.

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“…In fact, it had already been shown that the production of NO increases in proportion to the intensity of physical exercise until exhaustion and that regular training induces an increase in the concentration of salivary NO [25]. Endothelial NO synthase production in vascular endothelial cells is a result of higher blood flow to the active tissue [26]. For this reason, we hypothesize that the increase in blood flow in athletes during exercise is an important factor stimulating NO production in the vessels; however, we did not measure blood flow.…”

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“…Endothelial function is improved with exercise even in the absence of changes in classical risk factors like lipids levels, blood pressure, glucose or BMI (Green et al 2008). Acute-and moderate-intensity exercises increase shear stress, which stimulates endothelium-dependent vasodilatation through the increased synthesis of nitric oxide (Erkens et al 2017). Regular exercise training also leads to increased coronary artery size and dilatation capacity (Haskell et al 1993) and increased luminal diameter of conduit arteries (Green et al 2008).…”

High‐dose nitroglycerin administered during rewarming preserves erythrocyte deformability in cardiac surgery with cardiopulmonary bypass

“…NO participates in regulating vascular tone, blood perfusion, and adaptive response to shear forces . Disruption of NO may impair organ perfusion and thereafter induce tissue ischemia .…”