Activación selectiva de Na_V1.3 restaura la contractilidad linfática en la edad y la lesión

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 (Na _V ) channels drive cardiomyocyte excitability, their role in lymphatic muscle cell (LMC) physiology is not well defined. We identified Na _V 1.3, a Na _V 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. We tested whether selective Na _V 1.3 activation restores impaired lymphatic pumping in aging and radiation injury.

Na _V 1.3 expression in LMCs was confirmed through single-cell RNA sequencing analysis and immunostaining of mouse and human lymphatic vessels. Lymphatic contractility was quantified by in vivo fluorescence lymphangiography and interstitial fluid clearance was measured with a new bioluminescence assay. Na _V 1.3 function was assessed in young, aged, and radiation-injured mice. Na _V 1.3 knockout ( Scn3a ^-/- ) mice established the requirement of Na _V 1.3 for basal lymphatic excitability and responsiveness to the Na _V 1.3-specific activator, Tf2.

In mouse and human lymphatic vessels, Na _V 1.3 is expressed in adult LMCs. Although dispensable for basal lymphatic contractions, Na _V 1.3 acted as a pharmacologically recruitable reserve that amplified contractile output. Acute Na _V 1.3 activation with Tf2 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 Scn3a ^-/- mice, confirming Na _V 1.3 dependence.

Na _V 1.3 is a selectively druggable ion channel in adult lymphatic muscle that can be recruited to restore lymphatic pump function across aging and injury. Targeted Na _V 1.3 activation provides a molecular entry point for treating diseases characterized by lymphatic pump failure, a domain with no existing pharmacologic therapies.