The lymphangion: a not so ‘primitive’ heart

Knowledge regarding the mechanisms by which lymph is transported to the blood circulation has markedly advanced from a system originally considered driven by extrinsic compression to one where intrinsic constrictions of lymphatic chambers termed ‘lymphangions’ are recognised as a primary means for propelling lymph. Lymphangions arise through vessels being formed into multiple chambers through frequently occurring unidirectional valves, with pumping mediated by contractions of the circularly oriented smooth muscle in the vessel walls, each chamber acting like a ‘primitive heart’ (Fig. 1). The report by Lee et al. (2014) in this issue of The Journal of Physiology provides insight into the identity and role of two key types of Ca²⁺ channel in lymphangions, findings that indicate close analogy to the function of these channels in the heart.

Figure 1. The intrinsic lymphatic pump.

Photomicrographs of lymphangions, the heart-like chambers by which lymphatic vessels intrinsically propel lymph, showing: all three lymphangions delineated by valves (i.e. at narrow regions) in relaxed state (A), central lymphangion in constricted state (B), rightmost lymphangion in constricted state (C), and all lymphangions in constricted state (D) (reproduced from van Helden, 1993; perfused guinea pig mesenteric lymphatic vessel studied in vitro; scale: image width 2 mm).

PCR analysis of one of these, the L-type Ca²⁺ channel, provides evidence that three of the known four channel isoforms are present at the mRNA level. They also further examined one of these isoforms (Ca_V1.2) by immunohistochemistry showing that the protein is expressed in the smooth muscle. Ca_V1.2 is also the dominant Ca²⁺ channel in cardiac muscle (Catterall et al. 2005). Findings made by Lee et al. confirm that L-type Ca²⁺ channels subserve a fundamental role in mediating contraction but a minimal role if any in lymphatic pacemaking. This parallels the function of this channel in the heart.

The second channel studied was the T-type Ca²⁺ channel. There was minimal previous information on this channel in lymphatic vessels so the Lee et al. study provides long-overdue insight into this. They detected transcripts for two of the three T-type Ca²⁺ channel isoforms, with immunohistochemical studies for Ca_V3.2 demonstrating its presence near to or in lymphatic smooth muscle. Notably, they report that T-type Ca²⁺ channels have a role in lymphatic pacemaking, a role that has long been established for this channel type in the heart (Hagiwara et al. 1988).

This raises an interesting question that relates to lymphatic pacemaking. Traditionally, lymphatic pacemaking was proposed to be driven by voltage-dependent channel mechanisms in the cell membrane (Ward et al. 1989), similar to those proposed for heart pacemaking. However, recordings from near isopotential segments of lymphatic smooth muscle revealed a very different clock mechanism, one driven by Ca²⁺ release from intracellular Ca²⁺ stores (van Helden, 1993). Interestingly, since then a cardiac pacemaker mechanism driven by intracellular Ca²⁺ stores has been highlighted from studies in sinoatrial node pacemaker cells (Bogdanov et al. 2001). It turns out that this mechanism was an implicit property of earlier heart pacemaker models but was largely overlooked as, unlike in lymphangions, it did not maintain pacemaking by itself (Noble et al. 2010). Despite this it is clearly of importance and it is now recognised that heart pacemaking operates through two very different pacemaker clocks that symbiotically work together to drive heart pacemaking. The finding by Lee et al. that T-type Ca²⁺ channels have a role in lymphatic pacemaking indicates further parallels between lymphatic and cardiac pacemaker mechanisms because it suggests that lymphatic pacemaking is not only driven by an intracellular store-based Ca²⁺ clock but also by a cell membrane pacemaker clock involving T-type Ca²⁺ channels.

Parallelism between lymphatic and cardiac pacemaker mechanisms has also been proposed through the hypothesis that rhythmic lymphatic pacemaking is driven by a distinct syncytium of pacemaker cells, as is the case for the heart. However, to date there has been no convincing evidence that this is the case. The much lower membrane potential of lymphatic smooth muscle, which is similar to that of cardiac pacemaker cells, together with the smooth muscle localisation of T-type Ca²⁺ channels, as indicated by the Lee et al. data, suggests that here there may be divergence from the heart model, with the possibility that the smooth muscle paces itself.

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Competing interests

None declared.