Biology subjects

Ruscic, K. J.

Publications and source records attributed to Ruscic, K. J..

3 recordsLinked to original sources

bioRxiv2025

Selective Activation of NaV1.3 Restores Lymphatic Contractility in Age and Injury

BackgroundIntrinsic 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, 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. We tested whether selective NaV1.3 activation restores impaired lymphatic pumping in aging and radiation injury. MethodsNaV1.3 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. NaV1.3 function was assessed in young, aged, and radiation-injured mice. NaV1.3 knockout (Scn3a-/-) mice established the requirement of NaV1.3 for basal lymphatic excitability and responsiveness to the NaV1.3-specific activator, Tf2. ResultsIn 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 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 NaV1.3 dependence. ConclusionsNaV1.3 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.

physiology↗

bioRxiv2024

A Multiresolution Approach with Method-Informed Statistical Analysis for Quantifying Lymphatic Pumping Dynamics

Despite significant strides in lymphatic system imaging, the timely diagnosis of lymphatic disorders remains elusive. One main cause for this is the absence of standardized, quantitative methods for real-time analysis of lymphatic contractility. Here, we address this unmet need by combining near-infrared lymphangiography imaging with an innovative analytical workflow. We combined data acquisition, signal processing, and statistical analysis to integrate traditional peak and-valley with advanced wavelet time-frequency analyses. Decision theory was used to evaluate the primary drivers of attributable variance in lymphangiography measurements to generate a strategy for optimizing the number of repeat measurements needed per subject to increase measurement reliability. This approach not only offers detailed insights into lymphatic pumping behaviors across species, sex and age, but also significantly boosts the reliability of these measurements by incorporating multiple regions of interest and evaluating the lymphatic system under various gravitational loads. By addressing the critical need for improved imaging and quantification methods, our study offers a new standard approach for the imaging and analysis of lymphatic function that can improve our understanding, diagnosis, and treatment of lymphatic diseases. The results highlight the importance of comprehensive data acquisition strategies to fully capture the dynamic behavior of the lymphatic system.

physiology↗

bioRxiv2023

Lymphatic muscle cells are unique cells that undergo aging induced changes

Lymphatic muscle cells (LMCs) within the wall of collecting lymphatic vessels exhibit tonic and autonomous phasic contractions, which drive active lymph transport to maintain tissue-fluid homeostasis and support immune surveillance. Damage to LMCs disrupts lymphatic function and is related to various diseases. Despite their importance, knowledge of the transcriptional signatures in LMCs and how they relate to lymphatic function in normal and disease contexts is largely missing. We have generated a comprehensive transcriptional single-cell atlas--including LMCs--of collecting lymphatic vessels in mouse dermis at various ages. We identified genes that distinguish LMCs from other types of muscle cells, characterized the phenotypical and transcriptomic changes in LMCs in aged vessels, and uncovered a pro-inflammatory microenvironment that suppresses the contractile apparatus in advanced-aged LMCs. Our findings provide a valuable resource to accelerate future research for the identification of potential drug targets on LMCs to preserve lymphatic vessel function as well as supporting studies to identify genetic causes of primary lymphedema currently with unknown molecular explanation.

cell biology↗