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Increasing Pulmonary Artery Pulsatile Flow Improves Hypoxic Pulmonary Hypertension in Piglets

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Pulmonary Hypertension Promotes Neuroinflammation and Neurodegeneration.

Priscilla M De La Cruz^1,2, Angelia Lockett¹, Marta T Gomes¹

¹Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Indiana University, Indianapolis.

Biorxiv : the Preprint Server for Biology

|September 15, 2025

Summary

Pulmonary arterial hypertension (PAH) causes brain changes, including increased glial cells and reduced neurons. This study reveals TDP-43 protein mislocalization in the brain, a novel finding in PAH.

Keywords:

Neurodegeneration Neuroinflammation Pulmonary Hypertension TDP-43

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Area of Science:

Neuroscience
Cardiovascular Science
Pathology

Background:

Pulmonary arterial hypertension (PAH) is linked to neurocognitive deficits and brain abnormalities.
The underlying mechanisms connecting PAH to brain pathology are poorly understood.
TDP-43 proteinopathy is implicated in neurodegenerative diseases like FTLD and ALS.

Purpose of the Study:

To investigate the neuropathological changes in the brain associated with PAH.
To determine if PAH leads to gliosis, reduced neuronal density, and TDP-43 mislocalization.
To examine TDP-43 protein localization in human PAH brain tissue.

Main Methods:

Established rat models of PAH using monocrotaline or Sugen/Hypoxia.
Confirmed PAH via right heart catheterization.
Analyzed brain tissue for microglia (Iba1), astrocytes (GFAP), neurons (NeuN), and TDP-43.

Main Results:

PAH models exhibited increased microglia and astrocyte density in the frontal cortex.
Reduced neuronal density and neuronal TDP-43 mislocalization were observed in PAH rat brains.
Human PAH brain samples also showed neuronal TDP-43 mislocalization.

Conclusions:

PAH induces neuropathological changes including gliosis and neuronal loss.
The study provides the first evidence of TDP-43 proteinopathy in pulmonary arterial hypertension.
These findings suggest a potential link between PAH and neurodegenerative processes involving TDP-43.