The lymphangion: a not so 'primitive' heart.

Abstract

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 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 (CaV1.2) by immunohistochemistry showing that the protein is expressed in the smooth muscle. CaV1.2 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 CaV3.2 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.