VEGF ameliorates pulmonary hypertension through inhibition of endothelial apoptosis in experimental lung fibrosis in rats
Laszlo Farkas, Daniela Farkas, Kjetil Ask, Antje Möller, Jack Gauldie, Peter Margetts, Mark Inman, Martin Kolb
Laszlo Farkas, Daniela Farkas, Kjetil Ask, Antje Möller, Jack Gauldie, Peter Margetts, Mark Inman, Martin Kolb
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Research Article Pulmonology

VEGF ameliorates pulmonary hypertension through inhibition of endothelial apoptosis in experimental lung fibrosis in rats

Abstract

Idiopathic pulmonary fibrosis (IPF) can lead to the development of secondary pulmonary hypertension (PH) and ultimately death. Despite this known association, the precise mechanism of disease remains unknown. Using a rat model of IPF, we explored the role of the proangiogenic and antiapoptotic growth factor VEGF in the vascular remodeling that underlies PH. In this model, adenoviral delivery of active TGF-β1 induces pulmonary arterial remodeling, loss of the microvasculature in fibrotic areas, and increased pulmonary arterial pressure (PAP). Immunohistochemistry and mRNA analysis revealed decreased levels of VEGF and its receptor, which were inversely correlated with PAP and endothelial cell apoptosis in both the micro- and macrovasculature. Treatment of IPF rats with adenoviral delivery of VEGF resulted in reduced endothelial apoptosis, increased vascularization, and improved PAP due to reduced remodeling but worsened PF. These data show that experimental pulmonary fibrosis (PF) leads to loss of the microvasculature through increased apoptosis and to remodeling of the pulmonary arteries, with both processes resulting in PH. As administration of VEGF ameliorated the PH in this model but concomitantly aggravated the fibrogenic process, VEGF-based therapies should be used with caution.

Authors

Laszlo Farkas, Daniela Farkas, Kjetil Ask, Antje Möller, Jack Gauldie, Peter Margetts, Mark Inman, Martin Kolb

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Figure 2

Vascular remodeling and PA EC apoptosis in AdTGF-β1–induced PF.

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Vascular remodeling and PA EC apoptosis in AdTGF-β1–induced PF. (A and B...
(A and B) Medium-sized PA from AdTGF-β1 (A) and AdDL70 (B) rat, day 21. (C and D) Representative PA with caspase-3–positive EC (arrow) after AdTGF-β1 administration, day 7 (C), no caspase-3 immunoreactivity in PA after AdDL70 (D). Magnification, ×400. Scale bars: 50 μm. Vessels categorized according to ED: small, < 50 μm (E, G, and I); medium, 50 μm ≤ ED < 100 μm (F, H, and J). (E and F) Relative MWT of AdTGF-β1–induced PF (black bars). White bars, AdDL70. (G and H) Relative MWT of small (G) and medium (H) PA categorized according to PF degree. (I and J) Percentage of caspase-3–positive PA ECs in small (I) and medium (J) PA of AdTGF-β1 animals at day 7 categorized according to PF degree. Data were confirmed by IHC for cleaved caspase-3 (not shown). Each bar shows mean ± SEM of 3–4 animals per group (I and J) or 4–6 animals per group (E–H). *P < 0.05; **P < 0.01; ***P < 0.0001 (all versus AdDL70); †P < 0.05; ‡P < 0.01 (both versus Ashcroft 0-1); #P < 0.05; +P < 0.01 (1-way ANOVA).