Journal
PEDIATRIC RESEARCH
Volume 63, Issue 1, Pages 26-32Publisher
NATURE PUBLISHING GROUP
DOI: 10.1203/PDR.0b013e31815b690d
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Funding
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH &HUMAN DEVELOPMENT [K08HD046513] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR RESEARCH RESOURCES [C06RR015490] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL050147, T32HL007457, R01HL056046, R01HL044195, R01HL045990, R29HL056046] Funding Source: NIH RePORTER
- NCRR NIH HHS [C06 RR015490, C06 RR 15490] Funding Source: Medline
- NHLBI NIH HHS [HL-45990, T32 HL007457, R01 HL056046, HL-56046, HL-07457, R01 HL044195, HL-44195, R01 HL045990, HL-50147, R29 HL056046] Funding Source: Medline
- NICHD NIH HHS [K08 HD046513-02, K08 HD046513-01, K08 HD046513-05, K08 HD046513-03, K08 HD046513-04, K08 HD046513] Funding Source: Medline
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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% O-2) 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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