Emilin1 links TGF-β maturation to blood pressure homeostasis

Luca Zacchigna, Carmine Vecchione, Antonella Notte, Michelangelo Cordenonsi, Sirio Dupont, Silvia Maretto, Giuseppe Cifelli, Alessandra Ferrari, Angelo Maffei, Carla Fabbro, Paola Braghetta, Gennaro Marino, Giulio Selvetella, Alessandra Aretini, Claudio Colonnese, Umberto Bettarini, Giovanni Russo, Sandra Soligo, Maddalena Adorno, Paolo BonaldoDino Volpin, Stefano Piccolo, Giuseppe Lembo, Giorgio M. Bressan

Research output: Contribution to journalArticle

Abstract

TGF-β proteins are main regulators of blood vessel development and maintenance. Here, we report an unprecedented link between TGF-β signaling and arterial hypertension based on the analysis of mice mutant for Emilin1, a cysteine-rich secreted glycoprotein expressed in the vascular tree. Emilin1 knockout animals display increased blood pressure, increased peripheral vascular resistance, and reduced vessel size. Mechanistically, we found that Emilin1 inhibits TGF-β signaling by binding specifically to the proTGF-β precursor and preventing its maturation by furin convertases in the extracellular space. In support of these findings, genetic inactivation of Emilin1 causes increased TGF-β signaling in the vascular wall. Strikingly, high blood pressure observed in Emilin1 mutants is rescued to normal levels upon inactivation of a single TGF-β1 allele. This study highlights the importance of modulation of TGF-β availability in the pathogenesis of hypertension.

Original languageEnglish
Pages (from-to)929-942
Number of pages14
JournalCell
Volume124
Issue number5
DOIs
Publication statusPublished - Mar 10 2006

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

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    Zacchigna, L., Vecchione, C., Notte, A., Cordenonsi, M., Dupont, S., Maretto, S., Cifelli, G., Ferrari, A., Maffei, A., Fabbro, C., Braghetta, P., Marino, G., Selvetella, G., Aretini, A., Colonnese, C., Bettarini, U., Russo, G., Soligo, S., Adorno, M., ... Bressan, G. M. (2006). Emilin1 links TGF-β maturation to blood pressure homeostasis. Cell, 124(5), 929-942. https://doi.org/10.1016/j.cell.2005.12.035