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
Developmental Signaling Laboratory, Department of Histology Microbiology and Medical Biotechnologies, University of Padua, viale Colombo 3, 35121 Padua, Italy.
Cell. 2006 Mar 10;124(5):929-42. doi: 10.1016/j.cell.2005.12.035.
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.
转化生长因子-β（TGF-β）蛋白是血管发育和维持的主要调节因子。在此，我们基于对Emilin1基因敲除小鼠的分析，报道了TGF-β信号传导与动脉高血压之间前所未有的联系。Emilin1是一种在血管系统中表达的富含半胱氨酸的分泌型糖蛋白。Emilin1基因敲除动物表现出血压升高、外周血管阻力增加和血管尺寸减小。从机制上讲，我们发现Emilin1通过特异性结合前体TGF-β并阻止其在细胞外空间被弗林蛋白酶成熟来抑制TGF-β信号传导。支持这些发现的是，Emilin1的基因失活导致血管壁中TGF-β信号传导增加。令人惊讶的是，在单个TGF-β1等位基因失活后，Emilin1突变体中观察到的高血压恢复到正常水平。这项研究突出了调节TGF-β可用性在高血压发病机制中的重要性。
