# Critical Role for Microvasculature in Airway Transplantation

> **NIH NIH R01** · PALO ALTO VETERANS INSTIT FOR RESEARCH · 2020 · $483,194

## Abstract

PROJECT SUMMARY / ABSTRACT
The role of the lymphatic circulation in transplantation is complex. Properly functioning lymphatics promote
allograft health by clearing inflammatory infiltrates and edema fluid but also lead to accelerated rejection by
facilitating alloimmune trafficking to the draining lymph nodes. In the first two grant periods of this R01, we
have demonstrated how preserving blood microvessels may be a clinically-relevant strategy for preventing
chronic lung transplant rejection. How the health of the accompanying lymphatics might influence (positively or
negatively) the transplant's fate is still unknown. The purpose of this R01 competitive-renewal application is to
apply knowledge gleaned from new lymphedema and microvascular research to study the lymphatic
contribution to the overall allograft health.
In lung transplantation surgery, the lymphatics are severed and not surgically-reconnected. Preliminary studies
indicate that lymphangiogenesis, the growth of new lymphatics from the existing ones, drives the reconnection
of the donor and recipient lymphatic vessels and help the lymphatic vessels to regain their drainage function.
This “early lymphangiogenesis” event is harmful to transplants by promoting acute rejection through enhanced
alloimmune trafficking, especially when immune danger signals are high following organ implantation.
However, a “late lymphangiogenesis” response, occurring after immune priming when perioperative
inflammation has subsided, can be beneficial by efficiently resolving inflammation, restoring fluid balance and
inducing immune tolerance. Importantly, pilot results indicate that interfering with the “early
lymphangiogenesis” attenuates alloimmune responses, while inhibiting “late lymphangiogenesis” accelerates
rejection. Emerging evidence suggests that exogenously promoting “late lymphangiogenesis” (so-called
`therapeutic lymphangiogenesis') alleviates lung allograft rejection by attenuating inflammation and edema.
Hypoxia, VEGF-C/VEGFR3, Notch, and sphingosine-1-phosphate are the critical mediators of
lymphangiogenesis. Understanding how these mediators govern the function of lymphatic circulation can help
advance the concept of therapeutic lymphangiogenesis in transplantation. The global hypothesis of this grant is
that the biphasic contribution of the transplant lymphatic circulation, to both airway disease and health, is
governed by key lymphangiogenic pathways. Specific Aim 1 utilizes pharmacotherapy as well as lymphatic-
specific transgenic mice to investigate the concept that transplant lymphatics biphasically participate in both
disease pathogenesis and resolution. This aim investigates the roles of VEGF-C/VEGFR3, Notch, S1P and
hypoxia-related signaling pathways unique to the negative and positive properties of the lymphatic circulation
in airway transplants. Specific Aim 2 uses a series of adoptive cell transfer or deletion experiments and
tolerizing immunotherapy to test the hypothesis that t...

## Key facts

- **NIH application ID:** 9981770
- **Project number:** 5R01HL095686-10
- **Recipient organization:** PALO ALTO VETERANS INSTIT FOR RESEARCH
- **Principal Investigator:** Mark Robert Nicolls
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $483,194
- **Award type:** 5
- **Project period:** 2010-04-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9981770

## Citation

> US National Institutes of Health, RePORTER application 9981770, Critical Role for Microvasculature in Airway Transplantation (5R01HL095686-10). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9981770. Licensed CC0.

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