Journal
JOURNAL OF APPLIED PHYSIOLOGY
Volume 119, Issue 10, Pages 1164-1172Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/japplphysiol.00283.2015
Keywords
glycolysis; HIF; IL-6; fibroblast; macrophage
Categories
Funding
- National Heart, Lung, and Blood Institute [HL114887 (Axis), HL014985 (PPG), HL125827 (R01)]
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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 naive macrophages (M phi) 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 M phi (hereafter, termed FAM phi) exhibit aerobic glycolysis together with high expression of arginase 1, Vegfa, and I1lb, all of which require hypoxia-inducible factor 1 alpha and STAT3 signaling. Strikingly, in situ, the adventitial M phi phenotype in the remodeled PA closely resembles the M phi phenotype induced by fibroblasts in vitro (FAM phi), suggesting that FAM phi crosstalk involving metabolic and inflammatory signals is a critical, pathogenetic component of vascular remodeling. This review discusses metabolic and inflammatory changes in fibroblasts and M phi in PH with the goal of raising ideas about new interventions to abrogate remodeling in hypoxic forms of PH.
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