Hypoxia-induced pulmonary vascular remodeling requires recruitment of circulating mesenchymal precursors of a monocyte/macrophage lineage

Am J Pathol. 2006 Feb;168(2):659-69. doi: 10.2353/ajpath.2006.050599.


Vascular remodeling in chronic hypoxic pulmonary hypertension includes marked fibroproliferative changes in the pulmonary artery (PA) adventitia. Although resident PA fibroblasts have long been considered the primary contributors to these processes, we tested the hypothesis that hypoxia-induced pulmonary vascular remodeling requires recruitment of circulating mesenchymal precursors of a monocyte/macrophage lineage, termed fibrocytes. Using two neonatal animal models (rats and calves) of chronic hypoxic pulmonary hypertension, we demonstrated a dramatic perivascular accumulation of mononuclear cells of a monocyte/macrophage lineage (expressing CD45, CD11b, CD14, CD68, ED1, ED2). Many of these cells produced type I collagen, expressed alpha-smooth muscle actin, and proliferated, thus exhibiting mesenchymal cell characteristics attributed to fibrocytes. The blood-borne origin of these cells was confirmed in experiments wherein circulating monocytes/macrophages of chronically hypoxic rats were in vivo-labeled with DiI fluorochrome via liposome delivery and subsequently identified in the remodeled pulmonary, but not systemic, arterial adventitia. The DiI-labeled cells that appeared in the vessel wall expressed monocyte/macrophage markers and procollagen. Selective depletion of this monocytic cell population, using either clodronate-liposomes or gadolinium chloride, prevented pulmonary adventitial remodeling (ie, production of collagen, fibronectin, and tenascin-C and accumulation of myofibroblasts). We conclude that circulating mesenchymal precursors of a monocyte/macrophage lineage, including fibrocytes, are essential contributors to hypoxia-induced pulmonary vascular remodeling.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Actins / metabolism
  • Animals
  • Animals, Newborn
  • Antigens, CD / metabolism
  • Cattle
  • Cell Lineage
  • Cell Proliferation
  • Collagen Type I / metabolism
  • Fibroblasts / pathology
  • Fibroblasts / physiology
  • Fibronectins / metabolism
  • Hypertension, Pulmonary / metabolism*
  • Hypertension, Pulmonary / pathology
  • Hypoxia / metabolism*
  • Liposomes
  • Macrophages / physiology*
  • Male
  • Monocytes / physiology*
  • Muscle, Smooth, Vascular / metabolism
  • Pulmonary Artery / pathology
  • Pulmonary Circulation / physiology*
  • Rats
  • Rats, Inbred WKY
  • Stem Cells / physiology*
  • Tenascin / metabolism


  • Actins
  • Antigens, CD
  • Collagen Type I
  • Fibronectins
  • Liposomes
  • Tenascin