# Cholangiocyte-Derived Endothelin Signaling Mediates Biliary Injury and Liver Fibrosis

> **NIH VA IK2** · RLR VA MEDICAL CENTER · 2021 · —

## Abstract

The main goal of this application is to clarify the signaling mechanisms mediating biliary senescence
and angiogenesis during primary sclerosing cholangitis (PSC). It is known that (i) endothelin (ET)-1
signaling is enhanced in the bile duct ligation (BDL) model of obstructive cholestasis, (ii) it is primarily upregulated
in cholangiocytes and (iii) enhances liver fibrosis via hepatic stellate cell (HSC) activation. Outside of the liver,
ET-1 is a potent vasoconstrictor and enhances transforming growth factor-β1 (TGF-β1, pro-angiogenic factor)
expression in vascular endothelial cells (VECs). Overall, it is unknown how ET signaling (including ET-2 and ET-
3) mediate biliary senescence and VEC proliferation/angiogenesis during PSC. Additionally, changes in the
vascular bed and VEC proliferation during PSC is unknown. We found that ET-1, ET-2, ET-3 and ET-A and
ET-B are increased, particularly in cholangiocytes and VECs, in human PSC and the multidrug resistance-2
knockout (Mdr2-/-) mouse model of PSC. Furthermore, we have novel preliminary data showing increased VEC
proliferation and angiogenesis in both human PSC and in Mdr2-/- mice. Changes in angiogenesis versus
vasopenia during cholestasis is controversial, but considering PSC patients with portal hypertension have an
increased morbidity and mortality, there is likely some underlying VEC-mediated changes occurring. Therefore,
our novel findings are the first to indicate liver VEC proliferation and angiogenesis during PSC. Additionally,
these findings are the first to delve into ET signaling in cholangiocytes and VECs during PSC. We provide data
indicating a feedback loop, whereby ET signaling promotes TGF-β1 expression, which can in turn increase miR-
125b/HIF-1α expression, which is known to increase ET expression. These are the first data demonstrating a
positive feedback loop between ET/TGF-β1/miR-125b/HIF-1α that can perpetuate biliary senescence and liver
fibrosis in autocrine and paracrine manners. Furthermore, we found that inhibition of ET-A or ET-B in Mdr2-/-
mice using currently FDA-approved drugs (for the treatment of pulmonary hypertension) reduces biliary
senescence and liver fibrosis when compared to controls. Our overall hypothesis is that cholangiocytes and
liver VEC communicate with one another via endothelin ET/TGF-β1 signaling that increases biliary
senescence and VEC angiogenesis through autocrine and paracrine mechanisms. Our findings may lead
to the identification of new, effective therapeutics for the treatment of PSC. This application proposal is the first
step to developing independence for the PI, Dr. Lindsey Kennedy. This proposal elegantly marries the
background work of her mentors on cholangiocyte biology, microRNA signaling and angiogenesis with new
techniques and concepts that further delve into vascular biology during cholestasis. Following successful
completion of this application, Dr. Kennedy will have a better understanding of angiogenesis/vasopenia, VEC
biolo...

## Key facts

- **NIH application ID:** 10125064
- **Project number:** 1IK2BX005306-01
- **Recipient organization:** RLR VA MEDICAL CENTER
- **Principal Investigator:** Lindsey Kennedy
- **Activity code:** IK2 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2021-01-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10125064

## Citation

> US National Institutes of Health, RePORTER application 10125064, Cholangiocyte-Derived Endothelin Signaling Mediates Biliary Injury and Liver Fibrosis (1IK2BX005306-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10125064. Licensed CC0.

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