Emilin1 Links TGF-β Maturation to Blood Pressure Homeostasis

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.

Proprotein convertase furin/PCSK3 and atherosclerosis: New insights and potential therapeutic targets

“…Consistently, only furin is coexpressed with TGF-b1 in the developing heart, bones, and fetal liver [57]. Another study also showed that Emilin1 can inhibit TGFb1-induced signaling by preventing its furin-mediated cleavage, which is associated with decreased BP [58]. Taken together, these observations demonstrated that furin is the authentic enzyme responsible for TGF-b maturation, suggesting that the furin-TGF-b1 pathway may be the effective target for prevention and treatment of hypertension.…”

New insights into elastic fiber assembly

“…Similar to eln1/2 mice, emilin12/2 mice have significant high renin-induced hypertension and vessels with smaller diameters and thinner walls (Faury et al, 2003;Zacchigna et al, 2006). The absence of EMILIN-1 increases TGFb signaling and, interestingly, the vascular phenotype can be reversed by inactivating one TGF-b allele (emilin-12/2; tgf-b1/2 mice) (Zacchigna et al, 2006).…”

Vascular Smooth Muscle Emilin-1 Is a Regulator of Arteriolar Myogenic Response and Blood Pressure

“…1,2 All 4 proteins are expressed in the cardiovascular system, however, with significant differences concerning their fine distribution. 1,3,4 While Emilin-1 is expressed by endocardium and right ventricle myocytes and by cells of the entire blood vessel wall (endothelial cells [ECs], smooth muscle cells [SMCs] and adventitial fibroblasts), the other genes have a more restricted expression pattern: Emilin2 is active in myocardium, whereas Mmrn1 and Mmrn2 are expressed only by ECs in blood vessels and, in addition, in platelets and endocardial cells, respectively.…”

“…One prominent function of Emilin-1 is the regulation of systemic blood pressure (BP). 4 The protein, through its elastin microfibril interface domain, inhibits transforming growth factor (TGF)-β biosynthesis by blocking the proteolytic cleavage of the proTGF-β precursor into the latency associated peptide/TGF-β complex. The increase in TGF-β signaling induced by Emilin-1 deficiency results in systemic hypertension, accompanied by narrowing of arterial tree and structural alterations of the wall of elastic arteries.…”