Emilin1 links TGF-beta maturation to blood pressure homeostasis |
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| Authors: | Zacchigna Luca Vecchione Carmine Notte Antonella Cordenonsi Michelangelo Dupont Sirio Maretto Silvia Cifelli Giuseppe Ferrari Alessandra Maffei Angelo Fabbro Carla Braghetta Paola Marino Gennaro Selvetella Giulio Aretini Alessandra Colonnese Claudio Bettarini Umberto Russo Giovanni Soligo Sandra Adorno Maddalena Bonaldo Paolo Volpin Dino Piccolo Stefano Lembo Giuseppe Bressan Giorgio M |
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| Institution: | Developmental Signaling Laboratory, Department of Histology Microbiology and Medical Biotechnologies, University of Padua, viale Colombo 3, 35121 Padua, Italy. |
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| Abstract: | TGF-beta proteins are main regulators of blood vessel development and maintenance. Here, we report an unprecedented link between TGF-beta 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-beta signaling by binding specifically to the proTGF-beta precursor and preventing its maturation by furin convertases in the extracellular space. In support of these findings, genetic inactivation of Emilin1 causes increased TGF-beta signaling in the vascular wall. Strikingly, high blood pressure observed in Emilin1 mutants is rescued to normal levels upon inactivation of a single TGF-beta1 allele. This study highlights the importance of modulation of TGF-beta availability in the pathogenesis of hypertension. |
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