Hypoxia is a major cause of pulmonary hypertension (PH) worldwide, and it is likely that interstitial pulmonary macrophages contribute to this vascular pathology. We observed in hypoxia-exposed mice an increase in resident interstitial macrophages, which expanded through proliferation and expressed the monocyte recruitment ligand CCL2. We also observed an increase in CCR2 ⁺ macrophages through recruitment, which express the protein thrombospondin-1, which functionally activates TGF-β to cause vascular disease. Blockade of monocyte recruitment with either CCL2-neutralizing antibody treatment or CCR2 deficiency in the bone marrow compartment suppressed hypoxic PH. These data were supported by analysis of plasma samples from humans who traveled from low (225 m) to high (3500 m) elevation, revealing an increase in thrombospondin-1 and TGF-β expression following ascent, which was blocked by dexamethasone prophylaxis. In the hypoxic mouse model, dexamethasone prophylaxis recapitulated these findings by mechanistically suppressing CCL2 expression and CCR2 ⁺ monocyte recruitment. These data suggest a pathologic cross talk between 2 discrete interstitial macrophage populations, which can be therapeutically targeted.

Dysregulated metabolism characterizes both animal and human forms of pulmonary hypertension (PH). Enzymes involved in fatty acid metabolism have previously not been assessed in human pulmonary arteries affected by pulmonary arterial hypertension (PAH), and how inhibition of fatty acid oxidation (FAO) may attenuate PH remains unclear. Fatty acid metabolism gene transcription was quantified in laser-dissected pulmonary arteries from 10 explanted lungs with advanced PAH (5 idiopathic, 5 associated with systemic sclerosis), and 5 donors without lung diseases. Effects of oxfenicine, a FAO inhibitor, on female Sugen 5416-chronic hypoxia (SuHx) rats were studied in vivo using right heart catheterization, and ex vivo using perfused lungs and pulmonary artery ring segments. The impact of pharmacologic (oxfenicine) and genetic (carnitine palmitoyltransferase 1a heterozygosity) FAO suppression was additionally probed in mouse models of Schistosoma and hypoxia-induced PH. Potential mechanisms underlying FAO-induced PH pathogenesis were examined by quantifying ATP and mitochondrial mass in oxfenicine-treated SuHx pulmonary arterial cells, and by assessing pulmonary arterial macrophage infiltration with immunohistochemistry. We found upregulated pulmonary arterial transcription of 26 and 13 FAO genes in idiopathic and systemic sclerosis-associated PAH, respectively. In addition to promoting de-remodeling of pulmonary arteries in SuHx rats, oxfenicine attenuated endothelin-1-induced vasoconstriction. FAO inhibition also conferred modest benefit in the two mouse models of PH. Oxfenicine increased mitochondrial mass in cultured rat pulmonary arterial cells, and decreased the density of perivascular macrophage infiltration in pulmonary arteries of treated SuHx rats. In summary, FAO inhibition attenuated experimental PH, and may be beneficial in human PAH.

Right ventricular (RV) failure is the primary cause of death in pulmonary hypertension (PH), but the mechanisms of RV failure are not well understood. We hypothesized macrophages in the RV contribute to the RV response in PH. We induced PH in mice with hypoxia (FiO₂ 10%) and Schistosoma mansoni exposure, and in rats with SU5416‐hypoxia. We quantified cardiac macrophages in mice using flow cytometry. Parabiosis between congenic CD45.1/.2 mice or Cx3cr1‐green fluorescent protein and wild‐type mice was used to quantify circulation‐derived macrophages in experimental PH conditions. We administered clodronate liposomes to Sugen hypoxia (SU‐Hx) exposed rats to deplete macrophages and evaluated the effect on the extracellular matrix (ECM) and capillary network in the RV. In hypoxia exposed mice, the overall number of macrophages did not significantly change but two macrophage subpopulations increased. Parabiosis identified populations of RV macrophages that at steady state is derived from the circulation, with one subpopulation that significantly increased with PH stimuli. Clodronate treatment of SU‐Hx rats resulted in a change in the RV ECM, without altering the RV vasculature, and correlated with improved RV function. Populations of RV macrophages increase and contribute to RV remodeling in PH, including through regulation of the RV ECM.

Pulmonary arterial hypertension is a disease of the pulmonary vasculature, resulting in elevated pressure in the pulmonary arteries and disrupting the physiological coordination between the right heart and the pulmonary circulation. Exercise intolerance is one of the primary symptons of pulmonary arterial hypertension, significantly impacting the quality of life. The pathophysiology of exercise intolerance in pulmonary arterial hypertension is complex and likely multifactorial. Although the significance of right ventricle impairment and perfusion/ventilation mismatch is widely acknowledged, recent studies suggest pathophysiology of the skeletal muscle contributes to reduced exercise capacity in pulmonary arterial hypertension, a concept explored herein.

Background: Schistosomiasis is a major cause of pulmonary hypertension (PH) worldwide, and CD4 T cells are critical in disease pathogenesis. The role of dendritic cells (DCs) in Schistosoma-induced PH (SchPH) is unknown. There are two types of conventional DCs, cDC1 and cDC2, that prototypically activate CD8 and CD4 T cells, respectively. Methods: We exposed wildtype, DC reporter, and DC knockout mice to Schistosoma mansoni and quantified PH severity by heart catheterization and cell density by flow cytometry. Results: Experimental S. mansoni exposure increased the density of pulmonary DCs, particularly cDC2s. Deleting both cDC subsets did not significantly modify SchPH disease severity. Deleting only cDC1s caused more severe SchPH, associated with more Th2 CD4 and CD8 T cells. In contrast, deleting only cDC2s reduced SchPH disease severity. Conclusions: cDC1s appear to be protective, whereas cDC2s promote disease in SchPH.