title: Emilin1 links TGF-beta 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.
authors.affiliation: Developmental Signaling Laboratory, Department of Histology Microbiology and Medical Biotechnologies, University of Padua, viale Colombo 3, 35121 Padua, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Zacchigna
authors.forename: Carmine
authors.initials: C
authors.lastname: Vecchione
authors.forename: Antonella
authors.initials: A
authors.lastname: Notte
authors.forename: Michelangelo
authors.initials: M
authors.lastname: Cordenonsi
authors.forename: Sirio
authors.initials: S
authors.lastname: Dupont
authors.forename: Silvia
authors.initials: S
authors.lastname: Maretto
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cifelli
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ferrari
authors.forename: Angelo
authors.initials: A
authors.lastname: Maffei
authors.forename: Carla
authors.initials: C
authors.lastname: Fabbro
authors.forename: Paola
authors.initials: P
authors.lastname: Braghetta
authors.forename: Gennaro
authors.initials: G
authors.lastname: Marino
authors.forename: Giulio
authors.initials: G
authors.lastname: Selvetella
authors.forename: Alessandra
authors.initials: A
authors.lastname: Aretini
authors.forename: Claudio
authors.initials: C
authors.lastname: Colonnese
authors.forename: Umberto
authors.initials: U
authors.lastname: Bettarini
authors.forename: Giovanni
authors.initials: G
authors.lastname: Russo
authors.forename: Sandra
authors.initials: S
authors.lastname: Soligo
authors.forename: Maddalena
authors.initials: M
authors.lastname: Adorno
authors.forename: Paolo
authors.initials: P
authors.lastname: Bonaldo
authors.forename: Dino
authors.initials: D
authors.lastname: Volpin
authors.forename: Stefano
authors.initials: S
authors.lastname: Piccolo
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Lembo
authors.forename: Giorgio M
authors.initials: GM
authors.lastname: Bressan
mesh_terms: 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
chemical_list: 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