Let It Flow: Morpholino Knockdown in Zebrafish Embryos Reveals a Pro-Angiogenic Effect of the Metalloprotease Meprin α2Reportar como inadecuado




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Background

Meprin metalloproteases are thought to be involved in basic physiological functions such as cell proliferation and tissue differentiation. However, the specific functions of these enzymes are still ambiguous, although a variety of growth factors and structural proteins have been identified as meprin substrates. The discovery of meprins α1, α2 and β in teleost fish provided the basis for uncovering their physiological functions by gene silencing in vivo.

Methodology-Principal Findings

A Morpholino knockdown in zebrafish embryos targeting meprin α1 and β mRNA caused defects in general tissue differentiation. But meprin α2 morphants were affected more specifically and showed severe failures in the formation of the vascular system provoking the hypothesis of a pro-angiogenic effect. The blood circulation was largely diminished resulting in erythrocyte accumulation. These phenotypes mimic a previously described VEGF-A morphant, revealing a possible role of meprin α in VEGF-A activation. Indeed, human recombinant meprin α processed the vascular endothelial growth factor-A VEGF-A specifically, revealing the same cleavage products detectable for VEGF from zebrafish whole lysate.

Conclusions-Significance

Our results demonstrate that meprin metalloproteases are important for cell differentiation and proliferation already during embryogenesis, predominantly by the activation of growth factors. Thus, we conclude that meprins play a significant role in VEGF-A processing, subsequently regulating angiogenesis. Therefore, meprin α might be a new therapeutic target in cardiovascular diseases or in tumor growth inhibition.



Autor: André Schütte, Jana Hedrich, Walter Stöcker, Christoph Becker-Pauly

Fuente: http://plos.srce.hr/



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