At the high level, the lymphatic system has a lot in common with the vascular system. The cargo is lymph and immune cells rather than blood and immune cells, but the structure and function of vessels is quite similar. Both types of vessel are lined with endothelial cells, while a layer of smooth muscle manages contraction, dilation, and pulsation of vessels to manage volume, pressure, and fluid flow. Like blood vessels, lymphatic vessels exhibit dysfunction with age, such as in their ability to appropriately contract and dilate. This impairs fluid flow, producing a range of consequences. One of the more recently discovered issues is the impaired drainage of cerebrospinal fluid from the brain via the glymphatic system, a potentially important contribution to neurodegenerative conditions. There are others.
A great deal of effort has gone into developing drugs that influence the biochemistry regulating the action of smooth muscle in blood vessels, as this is one of the ways to force a reduction in high blood pressure. Now that researchers have compelling reasons to turn their focus towards analogous issues in the lymphatic system, there is a vast body of work to pull from, and many existing drugs and drug candidates to assess in animal studies. Interestingly, in today’s open access paper, researchers report considerable success in restoring the contractility of lymphatic vessels in aged mice by exploiting a mechanism that doesn’t occur in blood vessels. The results suggest that the specific approach taken should be developed and tested as a way to slow the onset of neurodegenerative conditions by restoring drainage of cerebrospinal fluid.
Selective Activation of NaV1.3 Restores Lymphatic Contractility in Age and Injury
Intrinsic lymphatic contractility is essential for tissue fluid balance, immunity, and organ function, yet no FDA-approved pharmacologic treatments specifically restore lymphatic contractility. Lymph is returned to the circulation by ion channel-driven cyclic contractions of collecting lymphatic vessels. Although voltage-gated sodium (NaV) channels drive cardiomyocyte excitability, their role in lymphatic muscle cell (LMC) physiology is not well defined. We identified NaV1.3 (also known as SCN3A), a NaV channel historically viewed as developmentally restricted and limited in adult tissues, as unexpectedly and selectively expressed in adult lymphatic muscle but absent from heart, vascular smooth muscle, and mature brain.
In mouse and human lymphatic vessels, NaV1.3 is expressed in adult LMCs. Although dispensable for basal lymphatic contractions, NaV1.3 acted as a pharmacologically recruitable reserve that amplified contractile output. Acute NaV1.3 activation with the NaV1.3-specific activator Tf2 (derived from scorpion venom) increased lymphangion ejection fraction and accelerated interstitial fluid clearance. Tf2 fully restored lymphatic pumping in aged mice and partially rescued radiation-induced contractile deficits. All Tf2 responses were abolished in NaV1.3 knockout mice, confirming NaV1.3 dependence.
In conclusion, NaV1.3 is a selectively druggable ion channel in adult lymphatic muscle that can be recruited to restore lymphatic pump function across aging and injury. Targeted NaV1.3 activation provides a molecular entry point for treating diseases characterized by lymphatic pump failure, a domain with no existing pharmacologic therapies.
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