Lymphatic myogenic constriction – how lymphatic vessels pump lymph uphill

Myogenic constriction in arterioles is defined as a decrease in vessel diameter in response to increase in blood pressure. This mechanism is necessary to protect downstream capillary beds against changes in blood pressure in order to maintain an appropriate capillary filtration rate. Arteriolar myogenic response is also an important contributor to blood flow autoregulation. Myogenic constriction in response to increase in intraluminal pressure has also been described in collecting lymphatic vessels (Hargens & Zweifach, 1977). In these vessels, increase in intraluminal pressure enhances the frequency of the rhythmical contractions that characterize these vessels (Hargens & Zweifach, 1977). This contraction–relaxation cycle, or lymphatic pumping, is the main driving force to propel lymph from the periphery back to the blood stream at the level of the subclavian veins. As this transport has to occur most of the time against a hydrostatic pressure gradient, lymph transport needs to rely on the strength of the rhythmical contractions and the resilience of competent valves to be efficient. Lymphatic valves, spaced along collecting lymphatic vessels, are exquisitely designed to prevent lymph flowing back into the preceding upstream chamber in order to ensure net proximal movement. New insights into the contractile activity and valve functions of collecting lymphatic vessels were recently reported in a set of studies published by the same research team (Davis et al. 2011, 2012; Scallan et al. 2012, 2013), using isolated lymphatic vessel from rat mesentery, a collecting vessel characterized by a potent rhythmical contractile activity as experimental model. In their latest study, in this issue of The Journal of Physiology, Scallan et al. (2013) used a preparation made of a segment flanked with two bordering valves left intact or only one valve in the middle of a segment pressurized via two canulae connected to each opening. The authors focused their investigation on the contractile responses of the chamber when the output/downstream pressure was raised in a stepwise manner above the input/upstream pressure, forcing the vessel to propel fluid against a pressure gradient, thus mimicking the physiologically relevant situation where lymph has to be propelled towards the heart against gravity. While contractile activity of the downstream/post-valve vessel segment was observed, as expected, to increase with the increase in output pressure, the authors observed that the pre-valve segment also constricted in response to the increase in output pressure. They convincingly showed that this constriction was myogenic in nature, reminiscent of the tonic response of arterioles to an increase in blood pressure, and also noticed that the constriction occurred even when the valve was closed, which should prevent the upstream segment from directly sensing the pressure change. This observation suggests that a signal generated in the downstream/post-valve segment is transmitted across the valve. Given the morphological structure and the anatomical characteristics of the lymphatic vessels, this information could travel via the muscle layer or via the endothelium. Similar to its role in modulation blood vessel tone, the endothelium is a critical player in the physiological modulation of lymphatic pumping and is the main cellular constituent of the valves. It could thus provide a logical path for information to travel between adjacent chambers. Likewise, lymphatic muscle cells have been reported to be continuous enough between most lymphatic chambers to allow electrical signals to be conducted equally well in upstream or downstream directions (Crowe et al. 1997). The authors chose to examine the role of the muscle layer and used an elegant approach to deliver pharmacological blockers in the lumen of the downstream chamber without affecting the upstream segment. In these conditions, the myogenic constriction and increase in contraction frequency of the upstream segment were abolished by altering either the contractions or the membrane potential of the muscle of the downstream chamber, suggesting the signal to be a depolarizing event conducted via the muscle layer. Membrane potential measurements were not performed and would be necessary to confirm these conclusions and identify the ionic conductance(s) involved. From a physiological point of view, the importance of this lymphatic myogenic constriction could be significant during the contraction–relaxation cycle. First, constriction of the pre-valve segment could preserve the valve function, avoiding its collapse in the face of an increase in downstream pressure. Second, constriction would help match the downstream pressure, providing the drive necessary to enable the valve to open, promoting fluid movement downstream. These effects would protect the upstream lymphatic vessels, particularly the muscle-lacking initial ones, from backflow and potentially damaging elevated pressure. The main function of this pre-valve myogenic constriction might thus be more important to preserve proper valve gating than resistance to flow as in resistive blood vessels (Scallan et al. 2013). These studies provide a necessary and better appreciation of the properties and function of the lymphatic vessels and their valves, and how this one-way system optimizes its contractile ability to accommodate lymph flow against a higher hydrostatic pressure. These findings are significant and need to be considered in the context of oedema and lymphoedema, a condition where lymph drainage is compromised, and where conditions could be exacerbated if valve function is impaired. Indeed, in an earlier study (Davis et al. 2011), the authors demonstrated that valve function became compromised in vessels distended by an increase in downstream pressure or when lymphatic pumping is altered, as occurs in lymphoedema. These findings, by stressing a role for pre-valve constriction, suggest that pharmacological means to increase/improve lymphatic tone could provide potential benefits to fight lymphoedema.

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