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Going with the flow: contextual fine‐tuning of vascular reactivity

Year: 2018
Type: article
Abstract: Autoregulation is the ability of a system to adjust its response to a particular stimulus. It is well established that autoregulation of blood flow is specifically important in maintaining proper tissue perfusion despite changes in arterial perfusion pressure. This phenomenon, known as the myogenic tone, depends on the ability of smooth muscle cells surrounding small-diameter arteries and arterioles to contract in response to increases in intravascular pressure. Moreover, smooth muscle cells mediating the myogenic response can be regulated by signalling molecules released from endothelial cells lining the vessels and by sympathetic nerves. This elaborate intercellular signalling process is essential for regulation of vascular reactivity and blood flow on a moment-to-moment basis. The mechanism of endothelium-dependent modulation of smooth muscle function involves several well-established pathways that contribute to muscle relaxation and vasodilatation, including electrical coupling through gap junctions and the release of diffusible factors such as nitric oxide. Conversely, sympathetic nerve stimulation regulates smooth muscle function, at least in part, by activating the Gq-coupled α1-adrenergic receptors in these cells. Gq activation stimulates phospholipase C to produce diacylglycerol and inositol 1,4,5-trisphosphate (IP3) thereby activating protein kinase C and IP3 receptors on the sarcoplasmic reticulum. Ultimately, this may elicit smooth muscle membrane depolarization resulting in an increase in intracellular Ca2+ ([Ca2+]i) and subsequent vasoconstriction. Direct stimulation of α1-adrenergic receptors with phenylephrine produces a similar contractile response. Interestingly, several studies report a concomitant increased in [Ca2+]i in both smooth muscle and endothelial layers during phenylephrine application, sympathetic nerve stimulation and depolarizing smooth muscle directly with high extracellular potassium (Dora et al. 1997; Nausch et al. 2012). Observations such as these suggest that signals from smooth muscle cells may propagate to endothelial cells through myoendothelial projections and that in doing so, these signals may regulate smooth muscle function and vascular reactivity. These observations led to the formulation of the aptly titled myoendothelial feedback mechanism (Dora et al. 1997; Nausch et al. 2012; Tran et al. 2012). This mechanism is thought to help prevent excessive vasoconstriction in response to stimuli inducing smooth muscle contraction (e.g. Gq-coupled receptor agonists and sympathetic nerve stimulation). The conceptual basis of the myoendothelial feedback mechanism posits that α1-adrenergic receptor activation increases [Ca2+]i and the concentration of second messengers such as IP3 in smooth muscle cells. The second messengers can then diffuse, via gap junctions, from smooth muscle cells to the myoendothelial projections where they trigger Ca2+ signalling in endothelial cells. These Ca2+ signals activate intermediate conductance, Ca2+-activated potassium channels (IK channels) in the myoendothelial projections. Activation of IK channels induces endothelial cell hyperpolarization, which in turn spreads retrogradely back to the smooth muscle cells to attenuate the initial vasoconstricting stimulus. Although there seems to be a consensus about the broad features of this mechanism, intense debate persists regarding the specific nature of the second messenger(s) involved, the necessary target(s), and the underlying Ca2+ signal(s) in endothelial cells (Dora et al. 1997; Nausch et al. 2012; Tran et al. 2012; Garland et al. 2017; Hong et al. 2018). Variances and discrepancies regarding myoendothelial feedback mechanisms could stem from differences in experimental conditions including the animal model, vessels, stimuli and preparations used in different investigations. In this issue of The Journal of Physiology, Wei and colleagues (2018) propose an intriguing hypothesis in which it is the inherent capacity of any given contractile stimulus to engage the endothelium that ultimately determines the contribution of myoendothelial feedback in limiting the vasoconstrictive response to that stimulus. A necessary corollary to this is that it is the nature of the vasoconstricting stimulus itself which determines the contribution of myoendothelial feedback in limiting vasoconstriction. To test this hypothesis, the authors investigated the contribution of myoendothelial feedback in limiting the contractile response of rat mesenteric arteries to several mechanistically distinct vasoconstrictor stimuli. As noted above, α1-adrenergic receptor stimulation leads to IK channel-dependent endothelial cell hyperpolarization, which subsequently limits the associated contractile response via myoendothelial feedback. Accordingly, IK channel-mediated myoendothelial feedback limited the contractile response of isolated mesenteric arteries to α1-adrenergic receptor activation produced by either nerve stimulation or application of exogenous noradrenaline. In contrast to α1-receptor stimulation, evidence showing IK channel-dependent changes in endothelial function during the contractile response to thromboxane A2 receptor activation or increased intraluminal pressure is lacking. As expected, and in agreement with the author's hypothesis, myoendothelial feedback did not limit the contractile response to thromboxane A2 receptor activation or increased intraluminal pressure. In addition to myoendothelial feedback, endothelial cells respond to numerous ligands as well as changes in shear stress along the vessel lumen. Thus, the authors sought to corroborate their isolated vessel observations in a physiologically relevant context where other endothelial regulatory mechanisms (e.g. shear stress) could take place. Interestingly, in the intact perfused mesenteric arterial bed, IK channel-dependent myoendothelial feedback appeared to play a minor role in limiting nerve-evoked vasoconstriction. Rather, shear stress-mediated activation of endothelial small conductance, Ca2+-activated potassium (SK) channels prevailed as the dominant mechanism. The authors conclude that while IK channel-dependent myoendothelial feedback could contribute to the local control of mesenteric arterial diameter, in the intact arterial bed, it is the activation of endothelial SK channels by shear stress, along with nitric oxide, which limits nerve-evoked vasoconstriction. This key observation reveals that in addition to the nature of the vasoconstrictor stimulus involved, the biological context in which that stimulus is operating is another determining factor underlying the endothelial mechanisms responsible for limiting vasoconstriction. Taken together, the data presented by Wei et al. suggest that the molecular mechanisms governing autoregulation of blood flow operate as a finely tuned stimulus and context-dependent functional network. None. Both authors have read and approved the final version of this manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. This work was supported by NIH grants R01HL098200 and R01HL121059 (to M.F.N.) and NIH grants R01HL111060 and R01HD087347 (to G.C.A.).
DOI: 10.1113/jp275924
Language: English
Field: Medicine
Open Access status: green
OpenAlex ID: W2794837900
FWCI:
Cites: 6
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Related to: 10