Journal of Applied Physiology
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J Appl Physiol 98: 714, 2005; doi:10.1152/japplphysiol.01298.2004
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COMMENTARY

HIGHLIGHTED TOPICS
Pulmonary Circulation and Hypoxia

Commentary

Exposure to chronic hypoxia, either persistent or intermittent, induces pulmonary hypertension and vascular remodeling in most mammalian species. Specifically, extensive fibroblast proliferation in the adventitial compartment in response to chronic hypoxia is common to many species including humans. In fact, fibroblasts within the pulmonary artery adventitia proliferate earlier and to a greater extent than other vascular cells in animals chronically exposed to hypoxia. Although several studies have shown that cultured fibroblasts from the pulmonary artery adventitia proliferate in response to hypoxia, the mechanisms through which hypoxia induces this autonomous growth phenotype have not been previously elucidated.

In the first featured article entitled, "Activation of phosphatidylinositol 3-kinase, Akt, and mammalian target of rapamycin is necessary for hypoxia-induced adventitial fibroblast proliferation," Dr. E. Gerasimovskaya and colleagues (2) determined that hypoxia activates phosphatidylinositol 3-kinase, Akt (PI3K/Akt); mammalian target of rapamycin (mTOR/p70S6K), and extracellular signal-regulated kinase (ERK1/2) signaling pathways in adventitial fibroblasts and that these pathways play a critical role in hypoxia-induced fibroblast proliferation. Activation of the mTOR/p70S6 pathway appears to be a necessary step and a key point of convergence for the ERK 1/2 and PI3K/Akt pathways that regulate cell cycle progression under hypoxic conditions. These findings suggest that, in certain cell types, hypoxic stimulation is capable of activating both transcriptional and translational pathways that are ultimately necessary for cell proliferation.

Transcription factors involved in regulating the proliferative responses of fibroblasts to hypoxia have not been previously defined. In the second featured article, entitled "Egr-1 antisense oligonucleotides inhibit hypoxia-induced proliferation of pulmonary artery adventitial fibroblasts," Dr. M. Banks and colleagues determined that the Egr-1 transcription factor was upregulated in the pulmonary artery adventitia under hypoxic conditions in vivo and that hypoxia upregulated Egr-1 protein expression in cultured adventitial fibroblasts. Using an Egr-1 antisense strategy, these investigators demonstrated that inhibition of Egr-1 protein expression was associated with a 50% decrease in cell proliferation. Furthermore, Egr-1 antisense oligonucleotides also inhibited such downstream mediators of cell proliferation as cyclin D and epidermal growth factor receptor.

Collectively, these two studies help illustrate the mechanisms through which a highly proliferative cell type can respond to hypoxia to regulate protein translational pathways and increase expression of downstream transcription factors to create an autonomous growth phenotype. They may also help explain early adventitial changes seen in hypoxic pulmonary hypertension.

Gary C. Sieck

Journal of Applied Physiology
February 2005, Volume 98

REFERENCES

  1. Banks MF, Gerasimovskaya EV, Tucker DA, Frid MG, Carpenter TC, and Stenmark KR. Egr-1 antisense oligonucleotides inhibit hypoxia-induced proliferation of pulmonary artery adventitial fibroblasts. J Appl Physiol 98: 732–738, 2005.[Abstract/Free Full Text]
  2. Gerasimovskaya EV, Tucker DA, and Stenmark KR. Activation of phosphatidylinositol 3-kinase, Akt, and mammalian target of rapamycin is necessary for hypoxia-induced adventitial fibroblast proliferation. J Appl Physiol 98: 722–731, 2005.[Abstract/Free Full Text]




This Article
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