Background: Pulmonary hypertension (PH) is associated with aberrant sympathoexcitation leading to right ventricular failure (RVF), arrhythmias, and death. Microglial activation and neuroinflammation have been implicated in sympathoexcitation in experimental PH. We recently reported the first evidence of thoracic spinal cord (TSC) neuroinflammation in PH rats. Here, we hypothesize that PH is associated with increased cardiopulmonary afferent signaling leading to TSC-specific neuroinflammation and sympathoexcitation. Furthermore, inhibition of TSC neuroinflammation rescues experimental PH and RVF.

Methods: We performed transcriptomic analysis and its validation on the TSC of monocrotaline (n=8) and Sugen hypoxia (n=8) rat models of severe PH-RVF. A group of monocrotaline rats received either daily intrathecal microglial activation inhibitor minocycline (200 μg/kg per day, n=5) or PBS (n=5) from day 14 through 28. Echocardiography and right ventricle-catheterization were performed terminally. Real-time quantitative reverse transcription PCR, immunolocalization, microglia+astrocyte quantification, and terminal deoxynucleotidyl transferase dUTP nick end labeling were assessed. Plasma catecholamines were measured by ELISA. Human spinal cord autopsy samples (Control n=3; pulmonary arterial hypertension n=3) were assessed to validate preclinical findings.

Results: Increased cardiopulmonary afferent signaling was demonstrated in preclinical and clinical PH. Our findings delineated common dysregulated genes and pathways highlighting neuroinflammation and apoptosis in the remodeled TSC and highlighted increased sympathoexcitation in both rat models. Moreover, we validated significantly increased microglial and astrocytic activation and CX3CL1 expression in TSC of human pulmonary arterial hypertension. Finally, amelioration of TSC neuroinflammation by minocycline in monocrotaline rats inhibited microglial activation, decreased proinflammatory cytokines, sympathetic nervous system activation and significantly attenuated PH and RVF.

Conclusions: Targeting neuroinflammation and associated molecular pathways and genes in the TSC may yield novel therapeutic strategies for PH and RVF.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10192067PMC
http://dx.doi.org/10.1161/HYPERTENSIONAHA.122.20782DOI Listing

Publication Analysis

Top Keywords

spinal cord
12
microglial activation
12
tsc neuroinflammation
12
thoracic spinal
8
neuroinflammation
8
novel therapeutic
8
pulmonary hypertension
8
increased cardiopulmonary
8
cardiopulmonary afferent
8
afferent signaling
8

Similar Publications

Blocking the p38 MAPK Signaling Pathway in the Rat Hippocampus Alleviates the Depressive-like Behavior Induced by Spinal Cord Injury.

ACS Chem Neurosci

January 2025

Jiangxi Key Laboratory of Neurological Diseases, Department of Neurosurgery, the first Affiliated Hospital, Jiangxi Medical College, Nanchang University, No. 17 Yongwaizheng Street, Nanchang, Jiangxi 330006, China.

Patients with spinal cord injury (SCI) may develop depression, which can affect their rehabilitation. However, the underlying mechanism of depression in SCI patients remains unclear. Previous studies have revealed increased p38 MAPK phosphorylation in the rat hippocampus after SCI, accompanied by depression-like behaviors.

View Article and Find Full Text PDF

Lower red blood cell count is a risk factor for higher D-dimer level in patients with spinal cord injury: A five year retrospective cross-sectional study.

J Spinal Cord Med

January 2025

Rehabilitation Medicine Center and Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, People's Republic of China.

Objectives: This study aims to elucidate the relationship between red blood cell (RBC) count and D-dimer levels in patients with spinal cord injury, with the goal of identifying potential therapeutic targets for minimizing D-dimer levels.

Study Design: An observational, retrospective, cross-sectional, single center study.

Setting: Individuals with SCI (576 cases) admitted to a rehabilitation medicine department.

View Article and Find Full Text PDF

Medial orbitofrontal cortex structure, function, and cognition associates with weight loss for laparoscopic sleeve gastrectomy.

Obesity (Silver Spring)

February 2025

Department of Radiology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.

Objective: The objective of this study was to investigate underlying mechanisms of long-term effective weight loss after laparoscopic sleeve gastrectomy (LSG) and effects on the medial orbitofrontal cortex (mOFC) and cognition.

Methods: A total of 18 individuals with obesity (BMI ≥ 30 kg/m) underwent LSG. Clinical data, cognitive scores, and brain magnetic resonance imaging scans were evaluated before LSG and 12 months after LSG.

View Article and Find Full Text PDF

Progress in spinal cord organoid research: advancing understanding of neural development, disease modelling, and regenerative medicine.

Biomater Transl

November 2024

Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Department of Orthopedics, Tongji Hospital affiliated to Tongji University, School of Life Science and Technology, Tongji University, Shanghai, China.

Stem cell-derived spinal cord organoids (SCOs) have revolutionised the study of spinal cord development and disease mechanisms, offering a three-dimensional model that recapitulates the complexity of native tissue. This review synthesises recent advancements in SCO technology, highlighting their role in modelling spinal cord morphogenesis and their application in neurodegenerative disease research. We discuss the methodological breakthroughs in inducing regional specification and cellular diversity within SCOs, which have enhanced their predictive ability for drug screening and their relevance in mimicking pathological conditions such as neurodegenerative diseases and neuromuscular disorders.

View Article and Find Full Text PDF

Background: Community integration (CI) is the ultimate goal of rehabilitation for individuals with disabilities. It plays a significant role in restoring their social functioning and facilitating their reintegration into community and family life. However, no studies have utilized bibliometric methods to explore community integration.

View Article and Find Full Text PDF

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!