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

• 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
• ISSN: 2045-8932; 2045-8940; 2045-8940
• DOI: 10.1086/679704

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.