The Sugen 5416/hypoxia mouse model of pulmonary hypertension revisited: long-term follow-up

PVRI Member Authors: Georg Hansmann, Stella Kourembanas

Abstract

The combination of a vascular endothelial growth factor receptor antagonist, Sugen 5416 (SU5416), and chronic hypoxia is known to cause pronounced pulmonary hypertension (PH) with angioobliterative lesions in rats and leads to exaggerated PH in mice as well. We sought to determine whether weekly SU5416 injections during 3 weeks of hypoxia leads to long-term development of angioobliterative lesions and sustained or progressive PH in mice. Male C57BL/6J mice were injected with SU5416 (SuHx) or vehicle (VehHx) weekly during 3 weeks of exposure to 10% oxygen. Echocardiographic and invasive measures of hemodynamics and pulmonary vascular morphometry were performed after the 3-week hypoxic exposure and after 10 weeks of recovery in normoxia. SuHx led to higher right ventricular (RV) systolic pressure and RV hypertrophy than VehHx after 3 weeks of hypoxia. Ten weeks after hypoxic exposure, RV systolic pressure decreased but remained elevated in SuHx mice compared with VehHx or normoxic control mice, but RV hypertrophy had resolved. After 3 weeks of hypoxia and 10 weeks of follow-up in normoxia, tricuspid annular plane systolic excursion was significantly decreased, indicating decreased systolic RV function. Very few angioobliterative lesions were found at the 10-week follow-up time point in SuHx mouse lungs. In conclusion, SU5416 combined with 3 weeks of hypoxia causes a more profound PH phenotype in mice than hypoxia alone. PH persists over 10 weeks of normoxic follow-up in SuHx mice, but significant angioobliterative lesions do not occur, and neither PH nor RV dysfunction worsens. The SuHx mouse model is a useful adjunct to other PH models, but the search will continue for a mouse model that better recapitulates the human phenotype.

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Topics

Endothelin and Endothelium & Epithelium and Epithelial Transport
Growth Factors
Hypoxia/ Intermittent Hypoxia/ Hypoxia-Ischemia and Ischemia-Reperfusion Injury
Pulmonary Hypertension

Authors

Sally H. Vitali, Georg Hansmann, Chase Rose, Angeles Fernandez-Gonzalez, Annette Scheid, S. Alex Mitsialis, and Stella Kourembanas

Published in:

Pulmonary Circulation Vol 4: No 4 cover image

December 2014

Pulmonary Circulation Vol 4: No 4

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