Abstract
Hypoxia impairs normal neonatal pulmonary artery remodeling and alveolar development. Matrix metalloproteinase-2 (MMP-2), which regulates collagen breakdown, is important during development. Our objective was to test the hypothesis that hypoxia attenuates the normal postnatal increase in MMP-2 and evaluate alveolar development and pulmonary arterial remodeling in Mmp2−/− mice. C57BL/6 wild-type (WT), Mmp2+/−, Mmp2−/−, and MMP-inhibited (with doxycycline) mice were exposed to hypoxia (12% O2) or air from birth to 2 wk of age. Pulmonary arterial remodeling, alveolar development, and vascular collagen and elastin were evaluated. MMP-2 was estimated by quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay, immunohistochemistry, and zymography. We observed that 1) in WT mice, hypoxia led to thicker-walled pulmonary arteries and impaired alveolarization, accompanied by decreased MMP-2 and increased tissue inhibitor of metalloproteinases-2 (TIMP-2); 2) Mmp2−/− mice in air had thicker-walled arteries, impaired alveolarization, and increased perivascular collagen and elastin compared with WT; 3) hypoxia further inhibited alveolarization but did not alter arterial thickening in Mmp2−/− mice. Mmp2+/− and MMP-inhibited mice also had thicker-walled arteries than WT in air, but alveolarization was not different. We conclude that hypoxia reduces the postnatal MMP-2 increase in the lung, which may contribute to abnormal pulmonary arterial remodeling and impaired alveolarization.
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Abbreviations
- BPD:
-
bronchopulmonary dysplasia
- ECM:
-
extracellular matrix
- MMP-2:
-
matrix metalloproteinase-2 (gelatinase A)
- MMP-14:
-
matrix metalloproteinase-14 (MT1-MMP)
- TIMP-2:
-
tissue inhibitor of metalloproteinases-2
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Funded in part by NICHD K08 HD046513, ATS PH-06-006, CCRI Dr Rud Polhill grant, a Research Facilities Improvement Program Grant C06 RR 15490, and National Heart, Lung, and Blood Institute Grants HL-44195, HL-50147, HL-45990, HL-07457, HL-56046.
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Ambalavanan, N., Nicola, T., Li, P. et al. Role of Matrix Metalloproteinase-2 in Newborn Mouse Lungs under Hypoxic Conditions. Pediatr Res 63, 26–32 (2008). https://doi.org/10.1203/PDR.0b013e31815b690d
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DOI: https://doi.org/10.1203/PDR.0b013e31815b690d
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