Emilin1 Links TGF-β Maturation to Blood Pressure Homeostasis

SummaryTGF-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.