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 Emifin1 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-beta 1 allele. This study highlights the importance of modulation of TGF-beta availability in the pathogenesis of hypertension.
Emilin1 links TGF-beta maturation to blood pressure homeostasis / L., Zacchigna; C., Vecchione; A., Notte; M., Cordenonsi; S., Dupont; S., Maretto; G., Cifelli; A., Ferrari; A., Maffei; C., Fabbro; P., Braghetta; G., Marino; G., Selvetella; A., Aretini; Colonnese, Claudio; U., Bettarini; G., Russo; S., Soligo; M., Adorno; P., Bonaldo; D., Volpin; S., Piccolo; Lembo, Giuseppe; G. M., Bressan. - In: CELL. - ISSN 0092-8674. - ELETTRONICO. - 124:5(2006), pp. 929-942. [10.1016/j.cell.2005.12.035]
Emilin1 links TGF-beta maturation to blood pressure homeostasis
COLONNESE, Claudio;LEMBO, Giuseppe;
2006
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 Emifin1 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-beta 1 allele. This study highlights the importance of modulation of TGF-beta availability in the pathogenesis of hypertension.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
