Emilin1 links TGF-beta maturation to blood pressure homeostasis.
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.
Zacchigna
Luca
L
Developmental Signaling Laboratory, Department of Histology Microbiology and Medical Biotechnologies, University of Padua, viale Colombo 3, 35121 Padua, Italy.
Vecchione
Carmine
C
Notte
Antonella
A
Cordenonsi
Michelangelo
M
Dupont
Sirio
S
Maretto
Silvia
S
Cifelli
Giuseppe
G
Ferrari
Alessandra
A
Maffei
Angelo
A
Fabbro
Carla
C
Braghetta
Paola
P
Marino
Gennaro
G
Selvetella
Giulio
G
Aretini
Alessandra
A
Colonnese
Claudio
C
Bettarini
Umberto
U
Russo
Giovanni
G
Soligo
Sandra
S
Adorno
Maddalena
M
Bonaldo
Paolo
P
Volpin
Dino
D
Piccolo
Stefano
S
Lembo
Giuseppe
G
Bressan
Giorgio M
GM
D000818:Animals; D001158:Arteries / Q000166:cytology / Q000378:metabolism; D001794:Blood Pressure / Q000502:physiology*; D045683:Furin / Q000378:metabolism; D018628:Gene Dosage; D017930:Genes, Reporter; D006706:Homeostasis; D006801:Humans; D006973:Hypertension / Q000209:etiology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D055457:Nodal Protein; D010641:Phenotype; D011498:Protein Precursors / Q000378:metabolism; D017434:Protein Structure, Tertiary; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis / Q000196:embryology / Q000235:genetics / Q000378:metabolism
D008562:Membrane Glycoproteins; C526007:NODAL protein, human; D055457:Nodal Protein; C526008:Nodal protein, mouse; D011498:Protein Precursors; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; C030340:elastin microfibril interface located protein; D045683:Furin