Immune–metabolic crosstalk between T cells and interstitial macrophages drives pulmonary vascular remodeling in cardiometabolic HFpEF

Introduction

Pulmonary hypertension (PH) is a common and prognostically adverse complication in obese patients with heart failure with preserved ejection fraction (HFpEF). Cardiometabolic HFpEF-associated PH (PH-cHFpEF) is characterized by inflammation and metabolic dysregulation. Alterations in pulmonary immune cell populations, particularly T cells and interstitial macrophages (IMs), may sustain inflammation, and promote maladaptive vascular remodeling. However, their cellular interactions in the context of PH-cHFpEF remain poorly understood.

Purpose

To elucidate the roles of T cells and interstitial macrophages (IMs) in driving vascular inflammation and remodeling in PH-cHFpEF.

Methods

A murine PH-cHFpEF model was induced by combining a high-fat diet with L-NAME for 15 weeks. Right ventricular (RV) function, pulmonary pressures, and exercise capacity were evaluated by echocardiography, invasive hemodynamics, and treadmill testing. Pulmonary immune composition and transcriptional states were characterized using single-nucleus RNA sequencing (snRNA-seq). Spleen histology assessed systemic immune changes. Mechanistic assays were performed in palmitic acid (PA)-stimulated THP-1 monocytes to mimic metabolic stress.

Results

cHFpEF mice developed PH as shown by elevated pulmonary artery pressure, increased pulmonary artery resistance, extended right ventricular wall thickness, and diminished pulmonary artery acceleration time. SnRNA-seq revealed expansion and transcriptional reprogramming of immune cells. CD206⁺MHC-II⁺ macrophages displayed increased Atf3 and reduced Fkbp5 expression, consistent with activation of stress-resolution and tissue-repair programs alongside enhanced glucocorticoid sensitivity. T cells exhibited increased Hif1a and Ctla4 but reduced Il7r, indicative of hypoxia-driven exhaustion.

Spleens showed enlarged white pulp and greater spatial overlap of T and B cells, pointing to heightened adaptive immune activation, and this enlargement could already be detected at 8 weeks. Furthermore, immunofluorescence identified enlarged T cell clusters in PH-cHFpEF spleen. In vitro, PA-stimulated macrophages exhibited a predominantly pro-inflammatory phenotype with expression patterns paralleling in vivo findings, suggesting that metabolically stressed reparative IMs sustain low-grade inflammation that promotes vascular remodeling in PH-cHFpEF.

Conclusion

Cardiometabolic stress in PH-cHFpEF reprograms pulmonary macrophages and T cells toward chronic, low-grade inflammation that perpetuates vascular remodeling. Targeting the immune-metabolic axis may represent a therapeutic avenue to mitigate pulmonary hypertension in obese HFpEF patients.