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Let It Flow: Morpholino Knockdown in Zebrafish Embryos Reveals a Pro-Angiogenic Effect of the Metalloprotease Meprin α(2)

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 identifi...

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Detalles Bibliográficos
Autores principales: Schütte, André, Hedrich, Jana, Stöcker, Walter, Becker-Pauly, Christoph
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2809112/
https://www.ncbi.nlm.nih.gov/pubmed/20098618
http://dx.doi.org/10.1371/journal.pone.0008835
Descripción
Sumario: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 α(1), α(2) 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 α(1) and β mRNA caused defects in general tissue differentiation. But meprin α(2) 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.