# Altered Lymphatic Function and Development in Congenital Heart Disease

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2023 · $728,575

## Abstract

PROJECT SUMMARY / ABSTRACT
Aberrations in lymphatic structure and function are increasingly recognized as a significant source of morbidity
in a variety of disease states. For example, lymphatic abnormalities associated with congenital heart disease
(CHD) that result in increased pulmonary blood flow (PBF) include congenital or acquired chylothoraces, and
immunologic aberrations. Importantly, it is increasingly appreciated that lymphatic abnormalities are not only
associated with a variety of pulmonary diseases but participate in their pathogenesis. Recent recognition that
abnormal respiratory dysfunction often persists years after cardiac correction and is an independent risk factor
for mortality in adult CHD patients has brought renewed urgency to better understand the underlying lymphatic
pathobiology in CHD, which thus far remains largely unknown. We have previously used a clinically relevant
large animal model of CHD with increased PBF (shunt) in combination with isolated vessel reactivity of the
thoracic duct and primary lymphatic endothelial cell (LEC) culture, to demonstrate that chronically increased PBF
and the consequential increase in lymphatic flow, is associated with: 1) abnormal pulmonary lymphatic flow and
architecture; 2) increased mitochondrial reactive oxygen species (mtROS)-driven hypoxia inducible factor-1
(HIF-1) activity and metabolic reprograming to support cellular and proliferation; and 3) a KLF2-dependent
decrease in nitric oxide (NO) signaling. In this renewal application we will test our novel hypothesis that in the
setting of increased PBF, the mechanosensory channel Piezo1 plays a pivotal role sensing alterations in
lymphatic flow, triggering downstream increases in endothelin-1 (ET-1) and mtROS driven HIF-1a activity. This
results in decreased NO bioavailability and subsequent lymphatic dysfunction, that contributes to persistently
abnormal respiratory mechanics even after the cardiac defect has been repaired. In support of this hypothesis,
we present preliminary evidence demonstrating: 1) increased lymphatic endothelial Piezo1, ET-1, RhoA, and
mtROS in shunt LECs; 2) Piezo1-, ET-1-, and mtROS-dependent increases in HIF-1 in control LECs; 3) shunt
lambs have abnormal respiratory mechanics and lymphatic endothelial dysfunction that persists following closure
of the shunt, despite normalized hemodynamics, and 4) that treatment with a mitochondrially-targeted antioxidant
(mitoquinone, MitoQ) reverses the HIF-1 mediated shunt LEC phenotype in vitro and normalizes pulmonary
lymphatic architecture and function in vivo. This overall hypothesis will be tested in three inter-related, but
independent mechanistic aims, that utilize integrated physiologic, cellular, and molecular experiments. These
translational and targetable studies include: 1) whole animal hemodynamic physiologic studies, advanced
CT/MR imaging, and sophisticated pulmonary function testing, 2) ex vivo thoracic duct reactivity studies, and 3)
transcripti...

## Key facts

- **NIH application ID:** 10590656
- **Project number:** 5R01HL133034-07
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Sanjeev A. Datar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $728,575
- **Award type:** 5
- **Project period:** 2016-06-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10590656

## Citation

> US National Institutes of Health, RePORTER application 10590656, Altered Lymphatic Function and Development in Congenital Heart Disease (5R01HL133034-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10590656. Licensed CC0.

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