# Lymphatic pacemaking and pumping in lymphedema: function, dysfunction, and rescue

> **NIH NIH R01** · UNIVERSITY OF MISSOURI-COLUMBIA · 2021 · $636,362

## Abstract

Lymph transport occurs against a hydrostatic pressure gradient and thus relies critically on the intrinsic
contractile function of lymphatic muscle, the “active lymphatic pump”. Failure of this pump is associated with
many types of lymphedema. Little is known about why lymphatic vessels become dysfunctional, but clinical
studies reveal an elevated lymphatic diastolic pressure, enlarged diameter, impaired or absent contractions, and
incompetent valves. These findings point to both pacemaker and valve dysfunction as underlying causes. This
R01 renewal continues to address the ionic mechanisms of pacemaking in lymphatic vessels, with the ultimate
goal of developing methods to treat pacemaker and contractile dysfunction in lymphedema.
 In the previous funding period genetic methods were used to assess the roles of multiple ion channels in
mouse lymphatic smooth muscle and a critical role for Ano1 (TMEM16A) was found. SM-specific deletion
resulted in a 3-4-fold reduction in pacemaking frequency and blunting or abolition of the increase in frequency in
response to pressure elevation. This proposal continues to use tissue-specific and global mouse KO models to
answer questions about ion channels that act in concert with Ano1 to initiate pacemaking in lymphatic smooth
muscle cells (LMCs). It addresses not only how Ano1 is activated but also pressure-sensing mechanisms through
mechanosensitive ion channels or G-protein-coupled receptors (GPCRs). Optogenetic tools will be used
extensively for measuring intracellular Ca2+ events, uncaging Ca2+ or IP3 and triggering depolarization with
channel rhodopsin. The central hypothesis is that a membrane oscillator generates a repetitive cycle of
depolarization/repolarization to trigger lymphatic action potentials (APs) and this cycle is modulated by
mechanosensitive ionic conductances and by Gαq/11-mediated IP3 production / Ca2+ release.
 This hypothesis will be tested with 2 experimental aims and a numerical modeling aim to aid in the
interpretation and integration of the underlying mechanisms: 1) Elucidate the Ca2+ sensitive ionic mechanisms
that facilitate initiation of the lymphatic AP. Is another Ca2+-activated ion channel acting in combination with Ano1
to provide depolarization prior to AP firing? Is the slope of diastolic depolarization near the AP threshold
determined by Ca2+ release events? Is a Ca2+-independent membrane oscillator involving HCN and Kv7
channels acting in combination with Ano1 as part of the pacemaking mechanism? 2) Determine the pressure-
sensitive ionic mechanisms that regulate lymphatic pacemaking. Do mechanosensitive GPCRs coupled to Gαq/11
drive IP3 production to regulate Ano1? Do mechanosensitive ion channels modulate depolarization or
repolarization? In parallel, 3) Numerical models will be used to predict and verify ionic mechanisms that govern
pacemaking, including the shape of the LMC action potential, the effect of pressure on diastolic depolarization,
factors determining pacema...

## Key facts

- **NIH application ID:** 10076844
- **Project number:** 5R01HL122578-06
- **Recipient organization:** UNIVERSITY OF MISSOURI-COLUMBIA
- **Principal Investigator:** Michael John Davis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $636,362
- **Award type:** 5
- **Project period:** 2015-04-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10076844

## Citation

> US National Institutes of Health, RePORTER application 10076844, Lymphatic pacemaking and pumping in lymphedema: function, dysfunction, and rescue (5R01HL122578-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10076844. Licensed CC0.

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