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Updated: May 23, 2026
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Induction and Characterization of Pulmonary Hypertension in Mice using the Hypoxia/SU5416 Model
Published on: June 3, 2020
Chronic hypoxia induces right heart failure in caveolin-1-/- mice
J Agustin Cruz1, Eileen M Bauer, Andres I Rodriguez
1Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Summary
Mice lacking caveolin-1 (Cav-1) show accelerated right ventricular dysfunction under chronic hypoxia due to increased oxidative stress. Restoring Cav-1 or inhibiting nitric oxide synthase prevented these detrimental effects.
Area of Science:
- Cardiovascular Physiology
- Pulmonary Hypertension Pathophysiology
- Molecular Cardiology
Background:
- Caveolin-1 (Cav-1) deficiency leads to age-related pulmonary hypertension.
- Chronic hypoxia is a known model for pulmonary hypertension.
- Young Cav-1-/- mice lack baseline pulmonary hypertension, providing a model to study early disease development.
Purpose of the Study:
- To investigate the impact of chronic hypoxia on young Cav-1-/- mice.
- To elucidate the mechanisms underlying right ventricular (RV) dysfunction in this model.
- To assess the role of endothelial nitric oxide synthase (eNOS) uncoupling and oxidative stress.
Main Methods:
- Exposure of Cav-1-/- and wild-type (WT) mice to chronic hypoxia.
- Hemodynamic measurements including right ventricular systolic pressure (RVSP) and cardiac output.
- Histological analysis for RV hypertrophy and fibrosis.
- Molecular analysis of RV sarco(endo)plasmic reticulum Ca(2+)-ATPase 2a (SERCA2a) mRNA, eNOS uncoupling, and protein kinase G (PKG) nitration.
- Intervention with endothelial-specific Cav-1 transgene or nitric oxide synthase inhibition.
Main Results:
- Hypoxia initially increased RVSP similarly in both groups, but RVSP decreased in Cav-1-/- mice after three weeks, unlike in WT mice.
- Cav-1-/- mice exhibited decreased cardiac output, increased RV hypertrophy and fibrosis, reduced SERCA2a mRNA, and impaired RV function.
- Pulmonary vascular remodeling was minimal, and left ventricular function remained normal in hypoxic Cav-1-/- mice.
- Increased eNOS uncoupling and PKG tyrosine nitration were observed in the RV of Cav-1-/- mice.
- These adverse effects were ameliorated by endothelial Cav-1 expression or NOS inhibition.
Conclusions:
- In Cav-1-/- mice, chronic hypoxia exacerbates RV dysfunction through mechanisms involving eNOS uncoupling and increased oxidative/nitrosative stress.
- This stress modifies the RV response to pressure overload, leading to accelerated functional deterioration.
- Targeting eNOS uncoupling or restoring Cav-1 may offer therapeutic strategies for RV protection in pulmonary hypertension.
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