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Hypoxia-inducible factors promote alveolar development and regeneration.

Authors: Vadivel, A  Alphonse, RS  Etches, N  Van Haaften, T  Collins, JJ  O'Reilly, M  Eaton, F  Thebaud, B 
Citation: Vadivel A, etal., Am J Respir Cell Mol Biol. 2014 Jan;50(1):96-105. doi: 10.1165/rcmb.2012-0250OC.
Pubmed: (View Article at PubMed) PMID:23962064
DOI: Full-text: DOI:10.1165/rcmb.2012-0250OC

Understanding how alveoli and the underlying capillary network develop and how these mechanisms are disrupted in disease states is critical for developing effective therapies for lung regeneration. Recent evidence suggests that lung angiogenesis promotes lung development and repair. Vascular endothelial growth factor (VEGF) preserves lung angiogenesis and alveolarization in experimental O2-induced arrested alveolar growth in newborn rats, but combined VEGF+angiopoietin 1 treatment is necessary to correct VEGF-induced vessel leakiness. Hypoxia-inducible factors (HIFs) are transcription factors that activate multiple O2-sensitive genes, including those encoding for angiogenic growth factors, but their role during postnatal lung growth is incompletely understood. By inducing the expression of a range of angiogenic factors in a coordinated fashion, HIF may orchestrate efficient and safe angiogenesis superior to VEGF. We hypothesized that HIF inhibition impairs alveolarization and that HIF activation regenerates irreversible O2-induced arrested alveolar growth. HIF inhibition by intratracheal dominant-negative adenovirus (dnHIF-1alpha)-mediated gene transfer or chetomin decreased lung HIF-1alpha, HIF-2alpha, and VEGF expression and led to air space enlargement and arrested lung vascular growth. In experimental O2-induced arrested alveolar growth in newborn rats, the characteristic features of air space enlargement and loss of lung capillaries were associated with decreased lung HIF-1alpha and HIF-2alpha expression. Intratracheal administration of Ad.HIF-1alpha restored HIF-1alpha, endothelial nitric oxide synthase, VEGF, VEGFR2, and Tie2 expression and preserved and rescued alveolar growth and lung capillary formation in this model. HIFs promote normal alveolar development and may be useful targets for alveolar regeneration.

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CRRD Object Information
CRRD ID: 10395379
Created: 2015-09-03
Species: All species
Last Modified: 2015-09-03
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.