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., Z., C., V., A., N., M., C., S., D., S., M., G., C., A., F., A., M., C., F., P., B., G., M., G., S., A., A., Colonnese, C., U., B., G., R., S., S., M., A., P., B., et al.. - 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.
