Lung Dysfunction Causes Systemic Hypoxia in Estrogen Receptor β Knockout ($ER\beta^{-/-}$) Mice

Estrogen receptor β (ERβ) is highly expressed in both type I and II pneumocytes as well as bronchiolar epithelial cells. ERa is not detectable in the adult lung. Lungs of adult female ERβ knockout$(ER\beta^{-/-})$mice have already been reported to have fewer alveoli and reduced elastic recoil. In this article, we report that, by 5 months of age, there are large areas of unexpanded alveoli in lungs of both male and female$ER\beta^{-/-}$mice. There is increased staining for collagen and, by EM, abnormal clusters of collagen fibers are seen in the alveolar septa of$ER\beta^{-/-}$mice. Immunohistochemical analysis and Western blotting with lung membrane fractions of$ER\beta^{-/-}$mice revealed down-regulation of caveolin-1, increased expression of membrane type-1 metalloproteinase, matrix metalloproteinase 2 (active form), and tissue inhibitors of metalloproteinases 2. Hypoxia, measured by immunohistochemical analysis for hypoxia-inducible factor la and chemical adducts (with Hypoxyprobe), was evident in the heart, ventral prostate, periovarian sac, kidney, liver, and brain of$ER\beta^{-/-}$mice under resting conditions. Furthermore, both male and female adult$ER\beta^{-/-}$mice were reluctant to run on a treadmill and tissue hypoxia became very pronounced after exercise. We conclude that ERβ is necessary for the maintenance of the extracellular matrix composition in the lung and loss of ERβ leads to abnormal lung structure and systemic hypoxia. Systemic hypoxia may be responsible for the reported left and right heart ventricular hypertrophy and systemic hypertension in$ER\beta^{-/-}$mice.