Abstract
BackgroundSystemic neovascularization of the lung during chronic ischemia has been observed in all mammals studied. However, the proteins that orchestrate the complex interaction of new vessel growth and tunneling through lung tissue matrix have not been described. Although previous work has demonstrated the CXC chemokines are essential growth factors in the process of angiogenesis in mice and rats, key matrix proteins have not been identified.MethodsSince the degradation of chemokines has been shown to be dependent on metalloproteinases (MMP), we first surveyed gene expression patterns (real time RT-PCR) of several lung matrix proteins in DBA/J (D2) mice and C57Bl/6 (B6) mice, strains known to have divergent parenchymal responses in other lung disease models. We studied changes in the time course of MMP-12 activity in D2 and B6 mice. Functional angiogenesis was determined 14 days after the onset of complete left lung ischemia induced by left pulmonary artery ligation (LPAL), using fluorescent microspheres.ResultsOur results confirmed higher levels of MMP-12 gene expression in D2 mice relative to B6, which corresponded to a phenotype of minimal systemic angiogenesis in D2 mice and more robust angiogenesis in B6 mice (p < 0.01). MMP-12 activity decreased over the course of 14 days in B6 mice whereas it increased in D2 mice (p < 0.05). MMP-12 was associated largely with cells expressing the macrophage marker F4/80. Genetic deficiency of MMP-12 resulted in significantly enhanced neovascularization (p < 0.01 from B6).ConclusionTaken together, our results suggest macrophage-derived MMP-12 contributes to angiostasis in the ischemic lung.
Highlights
Systemic neovascularization of the lung during chronic ischemia has been observed in all mammals studied
Our results demonstrate that there are substantial differences in the rate of lung angiogenesis between B6 and D2 strains and that matrix metalloproteinases (MMP)-12 is overall angiostatic during lung ischemia
The expression levels of matrix metalloproteinase 2 (MMP-2) and MMP-12 genes were significantly higher in D2 mice by more than respectively, 20- and 3-fold on average relative to B6 mice
Summary
Systemic neovascularization of the lung during chronic ischemia has been observed in all mammals studied. The global gene expression profile and subsequent protein validation demonstrated that the ELR + CXC chemokines are upregulated early after the onset of ischemia, and are essential to the process of systemic neovascularization of the lung [2,3] These observations provide further support to the accumulating body of evidence demonstrating that the pro-angiogenic. The MMP family of zinc binding, Ca2+-dependent neutral endopeptidases can act individually or together to degrade extracellular matrix Of these proteins, MMP-2 (gelatinase A) and MMP-9 have been shown to work in tandem and appear to be essential during the early stages of angiogenesis in several models of hypoxic, ischemia-induced angiogenesis to promote tissue remodeling as well as growth factor activation [11,13]. A variety of other matrix proteins and protein fragments have been shown to induce both inflammation and angiogenesis in several models of ischemia-induced neovascularization [14,15]
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