Abstract
Lymphatic vessels rely on spontaneous lymphatic muscle cell (LMC) contractions and one-way intraluminal valves to efficiently pump lymph and return it into the bloodstream. Intraluminal pressure is known to regulate the contractile function of lymphatics, with pressure elevation leading to increased contraction frequency and decreased amplitude. Contractions are normally initiated by a dominant pacemaker and are highly entrained among strongly coupled LMCs. Previously, we found that connexin45 is the major connexin isoform mediating LMC-LMC electrical coupling. Lymphatics from mice lacking smooth muscle connexin45 display uncoordinated, impaired contractions. Here, we utilized this connexin45-deficient model, pressure myography, and recently developed, novel analytical tools to assess the effects of elevated downstream pressure on the number, location, and frequency of lymphatic pacemakers. Our results show that, in vessels from healthy controls, an increase in downstream pressure resulted in the recruitment/development of new pacemakers and increased contractile frequency while a dominant pacemaker continued to be observed. In contrast, vessels from connexin45-deficient mice displayed significantly more pacemakers, but none were dominant; this worsened with elevated downstream pressure. These results suggest a potential protective mechanism through which the lymphatic vasculature adapts to transient increases in downstream pressure, but which may not be sustained in scenarios with chronic elevated downstream pressure.
Highlights
It is appreciated that Starling forces are not normally in balance across most blood microvascular networks, resulting in net fluid filtration and protein leakage into the interstitium that must be corrected by the lymphatic system [1]
Once transport of the fluorescent tracer was visible in the collecting lymphatic network (Figure 1A left panel), the preparation and contraction pattern were allowed to stabilize at 37 ◦C for 10 minutes and fluorescence videos of contraction waves in afferent popliteal lymphatic vessels were recorded
These videos were processed and analyzed to construct two-dimensional Space Time Maps (STMs) that represented the local change in outside diameter as a function of time at each position along an entire lymphatic segment (Figure 1A right panel)
Summary
It is appreciated that Starling forces are not normally in balance across most blood microvascular networks, resulting in net fluid filtration and protein leakage into the interstitium that must be corrected by the lymphatic system [1]. After fluid and protein are taken up by the lymphatic capillaries, subsequent lymph transport depends in part on extrinsic forces (e.g., skeletal muscle contractions) and in part on the active contractions of collecting lymphatic vessels [2]. Critical to efficient lymph transport are the intrinsic spontaneous contraction of lymphatic muscle cells (LMCs), in combination with one-way lymphatic valves that prevent or retard lymph backflow [3,4,5]. The entrainment of LMC contraction waves occurs as a result of the rapid propagation of a pacemaking signal (i.e., action potential) from. We recently demonstrated that strong electrical coupling between LMCs, with minimal interaction of other surrounding cell networks (e.g., limited electrical coupling between LMCs and lymphatic endothelial cells (LECs)), is essential for the focal generation of pacemaking signals and their rapid and efficient propagation along the lymphatic wall. The entrainment of lymphatic contractions is mediated primarily by LMC-LMC electrical communication through Cx45 gap junctions [7]
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