title: Vascular endothelial growth factor receptor 3 signaling contributes to angioobliterative pulmonary hypertension.
abstract: 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.
authors.affiliation: Victoria Johnson Laboratory for Lung Research, Virginia Commonwealth University, Richmond, Virginia, USA.
authors.forename: Ayser
authors.initials: A
authors.lastname: Al-Husseini
authors.affiliation: Victoria Johnson Laboratory for Lung Research, Virginia Commonwealth University, Richmond, Virginia, USA.
authors.forename: Donatas
authors.initials: D
authors.lastname: Kraskauskas
authors.affiliation: VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia, USA.
authors.forename: Eleanora
authors.initials: E
authors.lastname: Mezzaroma
authors.affiliation: VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Nordio
authors.affiliation: Victoria Johnson Laboratory for Lung Research, Virginia Commonwealth University, Richmond, Virginia, USA.
authors.forename: Daniela
authors.initials: D
authors.lastname: Farkas
authors.affiliation: Victoria Johnson Laboratory for Lung Research, Virginia Commonwealth University, Richmond, Virginia, USA.
authors.forename: Jennifer I
authors.initials: JI
authors.lastname: Drake
authors.affiliation: VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia, USA.
authors.forename: Antonio
authors.initials: A
authors.lastname: Abbate
authors.affiliation: Department of Environmental and Occupational Health, Florida International University, Miami, Florida, USA.
authors.forename: Quentin
authors.initials: Q
authors.lastname: Felty
authors.affiliation: Victoria Johnson Laboratory for Lung Research, Virginia Commonwealth University, Richmond, Virginia, USA.
authors.forename: Norbert F
authors.initials: NF
authors.lastname: Voelkel
keywords: MAZ51; Sugen 5416; VEGF isoforms; VEGF receptor 3; capillary rarefaction; chronic hypoxia; right heart failure; sFlt-1