# A Molecular Approach to the Pathogenesis of Portal Hypertension

> **NIH NIH R01** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2024 · $470,590

## Abstract

Increased resistance to sinusoidal blood flow is an important component of early as well as advanced
portal hypertension. This results from an imbalance in intrahepatic vasoconstrictor and vasodilator molecules,
the latter including nitric oxide (NO). Our laboratory has been on the cutting edge of advances in
understanding the molecular basis for the imbalance in NO that occurs after liver injury. Seminal among our
discoveries is that there is a (dramatic and remarkable) reduction in endothelial NO synthase (eNOS)
dependent NO release by sinusoidal endothelial cells (SECs) after liver injury. Further, this “endothelialopathy”
is a critical feature of portal hypertension, especially early in disease.
 Our focus has been on understanding the mechanism underlying this defect. Preliminary data presented
in the current application has identified highly novel post-translational defects in eNOS in SECs after liver
injury, including reduced phosphorylation of eNOS caused by abnormalities in molecules that form a
macromolecular regulatory complex that controls eNOS function (including the following G protein coupled
receptor (GPCR) regulatory proteins: β-arrestins, GIT1 and now β-PIX). Additionally, many of these partners
are regulated during liver injury. In the current project, we will test the highly focused and innovative central
hypothesis that the GIT1/β-PIX complex and its partners play a fundamental role in regulating eNOS function.
 Therefore, overarching goals of this new project are twofold. First, we wish to uncover fundamental basic
mechanisms that regulate eNOS function. Secondly, with a future objective being to translate our work to
humans with liver disease, we wish to validate the importance of the proposed signaling pathways in vivo.
Therefore, our specific aims are as follows: We will (1) determine how β-PIX, as a GIT1 binding partner, exerts
a dual role in post-translational regulation of eNOS activity in normal versus injured SECs, and (2) we will
characterize the function of the GIT1/β-PIX complex partner, paxillin, in regulating eNOS function through
interaction with β-PIX and GIT1 after liver injury. The proposed experiments will uncover novel mechanistic
aspects of eNOS function and as such have fundamental therapeutic implications not only for patients with liver
disease and portal hypertension, but also for those with other vascular disorders.

## Key facts

- **NIH application ID:** 10815922
- **Project number:** 2R01DK113159-05A1
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** DON C. ROCKEY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $470,590
- **Award type:** 2
- **Project period:** 2024-02-15 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10815922

## Citation

> US National Institutes of Health, RePORTER application 10815922, A Molecular Approach to the Pathogenesis of Portal Hypertension (2R01DK113159-05A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10815922. Licensed CC0.

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