# Altered Lymphatic Function and Development in Congenital Heart Disease

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $574,310

## Abstract

PROJECT SUMMARY / ABSTRACT
Patients with congenital heart disease frequently exhibit increased pulmonary blood flow (PBF) that leads to
altered respiratory mechanics, respiratory distress and poor growth. Although it has been known for decades
that these patients also have altered pulmonary lymphatics, and that lymphatic dysfunction can contribute to
the disease course, investigations into the mechanisms that underlie these lymphatic aberrations are sparse.
The ultimate goal of this proposal is to better understand the mechanisms that regulate lymphatic function and
growth, in order to develop new treatments for these vulnerable patients. Using our established clinically
relevant ovine model of a congenital heart defect with increased PBF (shunt), we have shown that the resulting
increase in pulmonary lymph flow leads to impaired lymphatic endothelial signaling and disrupts the normal
post-natal function and development of the pulmonary lymphatic system. Specifically, we have found that
chronically increased PBF resulted in (1) impaired pulmonary lymphatic tone and flow associated with
decreased bioavailable NO; and, (2) aberrations in pulmonary lymphatic development associated with HIF- and
c-MYC-dependent accelerated growth and metabolic reprogramming. Importantly, an expanding body of
literature indicates that lymphatic vessel capacitance and pumping primarily dictate lymphatic function, and
supports the idea that endothelial NO signaling is an important modulator of lymphatic pump activity and flow.
Additionally, metabolic alterations are associated with pulmonary vascular remodeling in the setting of
pulmonary hypertension. Based on our findings, our overall hypothesis is that chronic exposure to
increased pulmonary blood and lymph flow leads to lymphatic endothelial dysfunction characterized
by disrupted NO signaling, resulting in decreased pulmonary lymphatic flow and abnormal postnatal
pulmonary lymphatic growth and development associated with metabolic remodeling. By integrating
whole animal, isolated vessel, cell culture, molecular and biochemical investigations, the proposal seeks to: 1)
elucidate the mechanisms underlying alterations in pulmonary lymphatic tone and flow induced by chronically
increased PBF; and 2) elucidate the mechanisms whereby HIF- and c-MYC interact to promote abnormal
postnatal pulmonary lymphatic growth and development in response to chronically increased PBF. These
experiments will establish an interdisciplinary research program aimed at incorporating novel insights with
respect to lymphatic biology into the care of critically ill children born with congenital heart disease. Our clinical
expertise, large animal model-driven research, cell culture expertise and molecular and metabolic research
capabilities uniquely position us to translate our findings into the care of these patients. Importantly, our
preliminary data suggest a possible therapeutic strategy to support lymphatic function in this setting.

## Key facts

- **NIH application ID:** 9940764
- **Project number:** 5R01HL133034-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Sanjeev A. Datar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $574,310
- **Award type:** 5
- **Project period:** 2016-06-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9940764

## Citation

> US National Institutes of Health, RePORTER application 9940764, Altered Lymphatic Function and Development in Congenital Heart Disease (5R01HL133034-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9940764. Licensed CC0.

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