Thrombospondin-1 Null Mice are Resistant to Hypoxia-Induced Pulmonary Hypertension

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Thrombospondin-1 Null Mice are Resistant to Hypoxia-Induced Pulmonary Hypertension

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Title: Thrombospondin-1 Null Mice are Resistant to Hypoxia-Induced Pulmonary Hypertension
Author: Ochoa, Cristhiaan D; Al-Ansari, Essam; Quinn, Deborah A; Yu, Lunyin; Hales, Charles Albert

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Citation: Ochoa, Cristhiaan D., Lunyin Yu, Essam Al-Ansari, Charles A. Hales, and Deborah A. Quinn. 2010. Thrombospondin-1 null mice are resistant to hypoxia-induced pulmonary hypertension. Journal of Cardiothoracic Surgery 5: 32.
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Abstract: Background and objective: Chronic hypoxia induces pulmonary hypertension in mice. Smooth muscle cell hyperplasia and medial thickening characterize the vasculature of these animals. Thrombospondin-1 null (TSP-1\(^{-/-}\)) mice spontaneously develop pulmonary smooth muscle cell hyperplasia and medial thickening. In addition, TSP-1 produced by the pulmonary endothelium inhibits pulmonary artery smooth muscle cell growth. Based on these observations we sought to describe the pulmonary vascular changes in TSP-1\(^{-/-}\) mice exposed to chronic hypoxia. Methods: We exposed TSP-1\(^{-/-}\) and wild type (WT) mice to a fraction of inspired oxygen (FiO2) of 0.1 for up to six weeks. Pulmonary vascular remodeling was evaluated using tissue morphometrics. Additionally, right ventricle systolic pressures (RVSP) and right ventricular hypertrophy by right ventricle/left ventricle + septum ratios (RV/LV+S) were measured to evaluate pulmonary hypertensive changes. Finally, acute pulmonary vasoconstriction response in both TSP-1\(^{-/-}\) and WT mice was evaluated by acute hypoxia and U-46619 (a prostaglandin F2 analog) response. Results: In hypoxia, TSP-1\(^{-/-}\) mice had significantly lower RVSP, RV/LV+S ratios and less pulmonary vascular remodeling when compared to WT mice. TSP-1\(^{-/-}\) mice also had significantly lower RVSP in response to acute pulmonary vasoconstriction challenges than their WT counterparts. Conclusion: TSP-1\(^{-/-}\) mice had diminished pulmonary vasoconstriction response and were less responsive to hypoxia-induced pulmonary hypertension than their wild type counterparts. This observation suggests that TSP-1 could play an active role in the pathogenesis of pulmonary hypertension associated with hypoxia.
Published Version: doi:10.1186/1749-8090-5-32
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