Metabolic reprogramming and inflammation act in concert to control vascular remodeling in hypoxic pulmonary hypertension

Abstract

Pulmonary hypertension (PH) is a complex, multifactorial syndrome that remains poorly understood despite decades of research. PH is characterized by profound pulmonary artery (PA) remodeling that includes significant fibro-proliferative and inflammatory changes of the PA adventitia. In line with the emerging concept that PH shares key features with cancer, recent work centers on the idea that PH results from a multistep process driven by reprogramming of gene-expression patterns that govern changes in cell metabolism, inflammation, and proliferation. Data demonstrate that in addition to PA endothelial cells and smooth muscle cells, adventitial fibroblasts from animals with experimental hypoxic PH and from humans with PH (hereafter, termed PH-Fibs) exhibit proinflammatory activation, increased proliferation, and apoptosis resistance, all in the context of metabolic reprogramming to aerobic glycolysis. PH-Fibs can also recruit, retain, and activate naïve macrophages (Mϕ) toward a proinflammatory/proremodeling phenotype through secretion of chemokines, cytokines, and glycolytic metabolites, among which IL-6 and lactate play key roles. Furthermore, these fibroblast-activated Mϕ (hereafter, termed FAMϕ) exhibit aerobic glycolysis together with high expression of arginase 1, Vegfa, and I1lb, all of which require hypoxia-inducible factor 1α and STAT3 signaling. Strikingly, in situ, the adventitial Mϕ phenotype in the remodeled PA closely resembles the Mϕ phenotype induced by fibroblasts in vitro (FAMϕ), suggesting that FAMϕ crosstalk involving metabolic and inflammatory signals is a critical, pathogenetic component of vascular remodeling. This review discusses metabolic and inflammatory changes in fibroblasts and Mϕ in PH with the goal of raising ideas about new interventions to abrogate remodeling in hypoxic forms of PH.

Keywords: HIF; IL-6; fibroblast; glycolysis; macrophage.

Fig. 1.

In line with the emerging concept that pulmonary hypertension (PH) shares key features with cancer, increasing evidence supports the idea that PH results from a multistep process driven by reprogramming genes that govern changes in cell metabolism, inflammation, and proliferation. Pulmonary artery adventitial fibroblasts from animals with experimental hypoxic PH and from humans with pulmonary arterial hypertension exhibit proinflammatory activation, increased proliferation, and apoptosis resistance, all in the context of metabolic reprogramming to aerobic glycolysis. These activated adventitial fibroblasts can recruit, retain, and activate macrophages (Mϕ) toward a distinct proinflammatory/proremodeling phenotype through the secretion of chemokines, cytokines, and other metabolites, including lactate. This fibroblast-activated Mϕ (FAMϕ) also exhibits a switch to aerobic glycolysis, which is regulated through a STAT3-hypoxia-inducible factor 1 (HIF1) signaling axis. Collectively, this fibroblast-FAMϕ signaling unit plays a critical role in the persistent inflammation and fibrosis that characterize certain forms of PH. HDAC, histone deacetylase; miR-124, microRNA 124; PTBP1, polypyrimidine tract-binding protein 1; TCA, tricarboxylic acid; PKM2, M2 isoform of pyruvate kinase; Glut1, glucose importer typically up-regulated in cells adapted to high glycolysis; PH-Fib, adventitial fibroblasts from animals with experimental hypoxic PH and from humans with PH; PTEN, phosphatase and tensin homolog; MCP1, monocyte chemoattractant protein 1; pSTAT3, phosphorylated STAT3; Arg1, arginine 1; TGFβ, transforming growth factor β.