title: Pneumonectomy combined with SU5416 induces severe pulmonary hypertension in rats.
abstract: The SU5416 + hypoxia (SuHx) rat model is a commonly used model of severe pulmonary arterial hypertension. While it is known that exposure to hypoxia can be replaced by another type of hit (e.g., ovalbumin sensitization) it is unknown whether abnormal pulmonary blood flow (PBF), which has long been known to invoke pathological changes in the pulmonary vasculature, can replace the hypoxic exposure. Here we studied if a combination of SU5416 administration combined with pneumonectomy (PNx), to induce abnormal PBF in the contralateral lung, is sufficient to induce severe pulmonary arterial hypertension (PAH) in rats. Sprague Dawley rats were subjected to SuPNx protocol (SU5416 + combined with left pneumonectomy) or standard SuHx protocol, and comparisons between models were made at week 2 and 6 postinitiation. Both SuHx and SuPNx models displayed extensive obliterative vascular remodeling leading to an increased right ventricular systolic pressure at week 6 Similar inflammatory response in the lung vasculature of both models was observed alongside increased endothelial cell proliferation and apoptosis. This study describes the SuPNx model, which features severe PAH at 6 wk and could serve as an alternative to the SuHx model. Our study, together with previous studies on experimental models of pulmonary hypertension, shows that the typical histopathological findings of PAH, including obliterative lesions, inflammation, increased cell turnover, and ongoing apoptosis, represent a final common pathway of a disease that can evolve as a consequence of a variety of insults to the lung vasculature.
authors.affiliation: Department of Physiology, VU University Medical Center, Amsterdam, the Netherlands; Department of Pulmonology, VU University Medical Center, Amsterdam, the Netherlands; and.
authors.forename: C M
authors.initials: CM
authors.lastname: Happé
authors.affiliation: Department of Physiology, VU University Medical Center, Amsterdam, the Netherlands; Department of Pulmonology, VU University Medical Center, Amsterdam, the Netherlands; and.
authors.forename: M A
authors.initials: MA
authors.lastname: de Raaf
authors.affiliation: Department of Physiology, VU University Medical Center, Amsterdam, the Netherlands; Department of Pulmonology, VU University Medical Center, Amsterdam, the Netherlands; and.
authors.forename: N
authors.initials: N
authors.lastname: Rol
authors.affiliation: Department of Physiology, VU University Medical Center, Amsterdam, the Netherlands; Department of Pulmonology, VU University Medical Center, Amsterdam, the Netherlands; and.
authors.forename: I
authors.initials: I
authors.lastname: Schalij
authors.affiliation: Department of Pulmonology, VU University Medical Center, Amsterdam, the Netherlands; and.
authors.forename: A
authors.initials: A
authors.lastname: Vonk-Noordegraaf
authors.affiliation: Department of Physiology, VU University Medical Center, Amsterdam, the Netherlands;
authors.forename: N
authors.initials: N
authors.lastname: Westerhof
authors.affiliation: School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: N F
authors.initials: NF
authors.lastname: Voelkel
authors.affiliation: Department of Pulmonology, VU University Medical Center, Amsterdam, the Netherlands; and.
authors.forename: F S
authors.initials: FS
authors.lastname: de Man
authors.affiliation: Department of Pulmonology, VU University Medical Center, Amsterdam, the Netherlands; and hj.bogaard@vumc.nl.
authors.forename: H J
authors.initials: HJ
authors.lastname: Bogaard
mesh_terms: D000818:Animals; D001794:Blood Pressure; D004195:Disease Models, Animal; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000473:pathology*; D007211:Indoles; D008297:Male; D011013:Pneumonectomy; D011758:Pyrroles; D017207:Rats, Sprague-Dawley
chemical_list: D007211:Indoles; D011758:Pyrroles; C116890:Semaxinib
keywords: SU5416; flow; hypoxia; pneumonectomy; pulmonary hypertension