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Circulating Bone Marrow‐Derived Mesenchymal Precursors Robustly Contribute to Lung Vascular Remodeling in Pathogenesis of Pulmonary Hypertension

Pulmonary hypertension (PH) is characterized by marked fibroproliferative changes in the pulmonary artery (PA). We studied if circulating bone‐marrow (BM)‐derived mesenchymal precursors contribute to vascular remodeling in PH. In rat and calf models of PH, chronic hypoxia induced a robust influx of circulating mesenchymal precursors (fibrocytes) into the PA wall. Their in vivo depletion in circulation resulted in attenuation of PA remodeling. BM origin and differentiation fate of these cells were studied in female freemartin calves, natural XX‐XY BM chimeras. In hypoxic freemartins, numerous Y‐chr+ (BM‐derived) cells were observed in the PA, some differentiated into mesenchymal cells. Using laser capture microdissection and RT‐PCR, we observed an early, persistent, and pulmonary‐specific upregulation of factors potentially involved in recruitment, retention and differentiation of fibrocytes (C5, FIZZ‐1, MCP‐1, IL‐18, ‐6, VEGF, SDF‐1, MMP‐9, ET1, TGFb1). In culture, fibrocyte‐like cells from PA of hypoxic, but not control, calves exhibited augmented growth, migratory capabilities, and secreted potent mitogens for resident PA SMC. These data demonstrate that circulating BM‐derived fibrocytes robustly contribute to pulmonary vascular remodeling in PH, and could serve as a selective pharmacological target in the treatment of PH.