Vascular endothelial growth factor receptor 3 signaling contributes to angioobliterative pulmonary hypertension

Vascular endothelial growth factor receptor 3 signaling contributes to angioobliterative pulmonary hypertension

The mechanisms involved in the development of severe angioobliterative pulmonary arterial hypertension (PAH) are multicellular and complex. Many of the features of human severe PAH, including angioobliteration, lung perivascular inflammation, and right heart failure, are reproduced in the Sugen 5416...

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Bibliographic Details
Published in:Pulmonary circulation Vol. 5; no. 1; pp. 101 - 116
Main Authors: Al-Husseini, Ayser, Kraskauskas, Donatas, Mezzaroma, Eleanora, Nordio, Andrea, Farkas, Daniela, Drake, Jennifer I., Abbate, Antonio, Felty, Quentin, Voelkel, Norbert F.
Format: Journal Article
Language:English
Published: London, England University of Chicago Press 01-03-2015
SAGE Publications
John Wiley & Sons, Inc
Subjects:
Antibodies
capillary rarefaction
Cell growth
chronic hypoxia
Complementary DNA
Endothelial cells
Hypoxia
Kinases
Lungs
MAZ51
Messenger RNA
Original Research
Protein isoforms
Pulmonary hypertension
Receptors
right heart failure
sFlt‐1
Stem cells
Sugen 5416
Vascular endothelial growth factor
VEGF isoforms
VEGF receptor 3
VEGF receptor 3
Sugen 5416
chronic hypoxia
VEGF isoforms
sFlt-1
capillary rarefaction
MAZ51
right heart failure
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Summary:The mechanisms involved in the development of severe angioobliterative pulmonary arterial hypertension (PAH) are multicellular and complex. Many of the features of human severe PAH, including angioobliteration, lung perivascular inflammation, and right heart failure, are reproduced in the Sugen 5416/chronic hypoxia (SuHx) rat model. Here we address, at first glance, the confusing and paradoxical aspect of the model, namely, that treatment of rats with the antiangiogenic vascular endothelial growth factor (VEGF) receptor 1 and 2 kinase inhibitor, Sugen 5416, when combined with chronic hypoxia, causes angioproliferative pulmonary vascular disease. We postulated that signaling through the unblocked VEGF receptor VEGFR3 (or flt4) could account for some of the pulmonary arteriolar lumen–occluding cell growth. We also considered that Sugen 5416–induced VEGFR1 and VEGFR2 blockade could alter the expression pattern of VEGF isoform proteins. Indeed, in the lungs of SuHx rats we found increased expression of the ligand proteins VEGF-C and VEGF-D as well as enhanced expression of the VEGFR3 protein. In contrast, in the failing right ventricle of SuHx rats there was a profound decrease in the expression of VEGF-B and VEGF-D in addition to the previously described reduction in VEGF-A expression. MAZ51, an inhibitor of VEGFR3 phosphorylation and VEGFR3 signaling, largely prevented the development of angioobliteration in the SuHx model; however, obliterated vessels did not reopen when animals with established PAH were treated with the VEGFR3 inhibitor. Part of the mechanism of vasoobliteration in the SuHx model occurs via VEGFR3. VEGFR1/VEGFR2 inhibition can be initially antiangiogenic by inducing lung vessel endothelial cell apoptosis; however, it can be subsequently angiogenic via VEGF-C and VEGF-D signaling through VEGFR3.
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ISSN:2045-8932
2045-8940
2045-8940
DOI:10.1086/679704