Lymph flow, valves and why lymph loading is so important

Recent findings that lymph flow influences the formation and maintenance of valves in the lymph collectors is a valuable piece in the jigsaw puzzle that is our understanding of lymph formation and transportation. For me it was one of those pieces that just slotted into a little gap and suddenly explains a lot.

The paper I'm referring to is on the genes involved in embryonic development and postnatal maintenance of valves in mice Yang et al (1). The results elucidate the role of adherin (molecules that help cells attach to one another) in valve formation and function, and while the paper is available open access, you'll need a molecular biology degree to read it. Click here read the paper.

Fortunately there is also a good summary in the USF Health News and an excellent webinar by one of the authors on the LE&RN website. The first half of the webinar is an overview of how lymph vessels are formed and function and worth watching for that alone. By half way though I felt myself go cross-eyed and skipped to the conclusion at the end. View the webinar.

“We knew that lymph flow was required for the valves to form and function throughout life, but we did not know how the endothelial cells that make up the inner lining of lymphatic vessels can ‘sense’ the flow" Joshua Scallan PhD

Another paper by Li and colleagues (2) describes the effect of lymph flow on lymphatic smooth muscle contractions. This is an in vitro model of a single lymphangion, so still not in humans, but they seem to have included a lot of known variants into the model. Models like this are important in developing hypotheses that can be further investigated and this model suggests that the co-ordination of the relaxation and contraction phases of the lymphangion are also influenced by lymph flow. Cyclical fluctuations in nitric oxide (NO) and calcium ions (Ca++) have a similar effect on smooth muscle in lymph and blood vessels, NO relaxes the muscle and promotes dilatation (filling) and Ca++ stimulates smooth muscle contractions (emptying).

So with the disclaimer that molecular biology is NOT my area of expertise, here is my attempt to put these findings together and work out what that means for our understanding of the effects of MLD on lymphmotoricity. The endothelial cells that line all lymph vessels are sensitive to stretch and shear forces and these conditions influence the levels of NO and Ca++ and other cytokines released into the lymph. The molecules that influence valve formation and function have their effect on adherins, which are the molecules that join the endothelial cells together. At the initial lymph vessel end of the system they form button junctions which allow gaps for lymph formation to occur. Further along in the collectors the cell junctions are in a zipper formation to restrict movement across the vessel wall. In the valves they have something to do with the stiffness or flexibility of the valve flap. Valves are generally held in an open state.

The effect of NO and Ca++ on smooth muscle within a single lymphangion, particularly in the pre-valve and post-valve regions can be seen in this video from the model created by Li and colleagues which shows the effect of fluctuating NO and Ca++ on smooth muscle contraction within a single lymphangion. Lymph is propelled forward by a sudden forceful contraction and passes through a few valves which are held open. Then as the lymph flow slows the chemical levels reset (watch the graphs at the top falling) eventually reaching threshold and another contraction is initiated. Just prior to contraction the angion relaxes fully and some re-fluxing lymph is pulled back though the open valves. This increases the load within the angion triggering the stretch receptor reflex and increasing the force and amplitude of the contraction. This video is cropped to 1 contraction, view the full 9 minute video here.

This video is an ICG image of lymph vessels in the ankle showing how this oscillating pattern of lymph flow looks over a chain of angions. We can see the 'parcels' of lymph being propelled along through a number of angions and then as the parcel slows you can see the load reflux a little to distend the angion wall, initiating the next propulsion of lymph along the chain of angions.

When we also consider what we know about the pathological changes occurring in the collector vessels during lymphoedema then we can see how under constant stress and protein exposure all layers of the vessel wall eventually succumb to fibrosis. With this new understanding of the importance of lymph flow in endothelial cell signalling, I can now appreciate how the interruption in lymph flow will result in the loss of valves, contribute to further interruption in lymph flow, and it's a downward spiral from there. The ageing lymph vessels as described by Shang et al is the most readable references for today (3). It is a fascinating account of the changes in lymph-motoricity and valve function make the new findings relevant and is really worth reading.

Taken together, these papers highlight the importance of continued lymph loading to maintain collector vessel health. If the oscillating nature of lymph flow is essential in normal vessel maintenance, then it must be crucial in recovery after acute damage or chronic stress. So how does this all relate to Dr Vodders' MLD?

Keeping in mind that these studies were not on the effects of MLD, what can we extrapolate to further our understanding of the way in which Vodder's MLD influences lymphatic function? Our current understanding is that the very precise movements of the skin stimulate lymph-motoricity via application of shearing forces into the tissue layers. (see a previous post on effects of different techniques). When we create movement around the initial lymph plexus without compressing these very superficial structures, we promote lymph formation which loads the system. The stretching and shearing forces applied to the lymph collectors have been shown to initiate stretch receptor mediated contractions of the smooth muscle. Systemically the reduction in sympathetic tonus dilates the lymph vessels allowing for increased filling which in turn increases the force and amplitude of the next contraction. Do these movements also increase NO in the lymph, and is this another factor in improved lymph flow?

Lymph vessels that are damaged during surgery or traumatic injury, and which do not reconnect or develop collateral pathways will deteriorate, and this understanding of the importance of lymph flow in valve maintenance and muscle contraction may explain how that happens. By gently helping to maintain lymph flow in these damaged vessels, MLD can help the system to recover from acute injury by loading the lymph vessels, maintaining valve health and encouraging the establishment of new pathways.

1. Yang, Y., et al. (2019). "VE-cadherin is required for lymphatic valve formation and maintenance." Cell reports 28(9): 2397-2412. e2394.

2. Li, H., et al. (2019). "The effects of valve leaflet mechanics on lymphatic pumping assessed using numerical simulations." Scientific Reports 9(1): 1-17.

3. Shang, T., et al. (2019). "Pathophysiology of aged lymphatic vessels." Aging (Albany NY) 11(16): 6602.https://www.aging-us.com/article/102213/text#fulltext