# Regulation of lymphatic muscle cell function by store operated calcium entry signaling

> **NIH NIH R01** · UNIVERSITY OF MISSOURI-COLUMBIA · 2024 · $587,042

## Abstract

PROJECT SUMMARY
Secondary lymphedema poses a significant financial and health burden afflicting 1 in 1000
Americans, resulting in a debilitating and incurable swelling and fibrosis in the affected extremity
or tissue. The prevailing hypothesis for the pathogenesis of secondary lymphedema posits a
role for lymphatic collecting vessel (cLV) pump failure in response to elevated lymphatic
pressures observed in LE patients, and points to a deficit in lymphatic muscle cell (LMC)
function. The process by which LMCs regulate pressure-dependent pacemaking, contractility,
and transcriptional regulation are critically dependent on inositol triphosphate receptor 1
(IP3R1)-dependent Ca2+ oscillations, although the mechanisms that sustain LMC Ca2+
homeostasis remain unexplored. The central goal of this proposal is to address this knowledge
gap and determine how LMC Ca2+ dynamics regulate contractile activity and transcriptional
adaptation to ensure fluid transport homeostasis. The Ca2+ source that refills the store has been
assumed to be only voltage-gated L-type channels, however our preliminary studies identified
the novel expression of the SR Ca2+ sensor proteins Stim1 and Stim2 as well as the plasma
membrane (PM) Ca2+ channels Orai1 and Orai3 in healthy LMCs, which are the critical
components of store operated Ca2+entry (SOCE). Our preliminary findings also show functional
SOCE in healthy LMCs in response to store depletion and that LMC Ca2+ oscillations are lost
when SOCE is inhibited. Intriguingly, robust SOCE activation by excessive vasocontractile
agonist signaling or SR Ca2+ leak drives cLVs into a contractile rigor and thus may contribute to
lymphatic dysfunction. This led us to hypothesize that SOCE is a key modulator of lymphatic
muscle cell function. We proposed the following aims to determine the role of SOCE in the
regulation of lymphatic contractility and transcriptional regulation. Specific Aim1: Assess SR-PM
junction formation and SOCE activity in LMCs. Specific Aim2: Determine the contribution of
SOCE to pressure-dependent LMC pacemaking and contractility. Specific Aim3: Investigate the
mechanisms by which IP3R1- Ca2+ oscillations and SOCE regulate LMC contractile protein
expression through Ca2+-dependent transcription factor activation such as nuclear factor of
activated T cells (NFATs). This project will provide novel information about the role of SOCE as
a fundamental Ca2+ homeostatic mechanism in LMCs and the degree to which SOCE is
required for acute and chronic cLV adaptation to pressure. These results will identify novel
targets for pharmacological intervention in LE patients and may shed light on cLV contractile
dysfunction reported in obesity, diabetes, and hypertension.

## Key facts

- **NIH application ID:** 10942329
- **Project number:** 1R01HL175083-01
- **Recipient organization:** UNIVERSITY OF MISSOURI-COLUMBIA
- **Principal Investigator:** Scott D. Zawieja
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $587,042
- **Award type:** 1
- **Project period:** 2024-08-01 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10942329

## Citation

> US National Institutes of Health, RePORTER application 10942329, Regulation of lymphatic muscle cell function by store operated calcium entry signaling (1R01HL175083-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10942329. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*