Loss of EMILIN-1 Enhances Arteriolar Myogenic Tone Through TGF-β (Transforming Growth Factor-β)-Dependent Transactivation of EGFR (Epidermal Growth Factor Receptor) and Is Relevant for Hypertension in Mice and Humans

Daniela Carnevale, Nicola Facchinello, Daniele Iodice, Dario Bizzotto, Marialuisa Perrotta, Diego De Stefani, Fabio Pallante, Lorenzo Carnevale, Franco Ricciardi, Giuseppe Cifelli, Francesco Da Ros, Manuel Casaburo, Stefania Fardella, Paolo Bonaldo, Gualtiero Innocenzi, Rosario Rizzuto, Paola Braghetta, Giuseppe Lembo, Giorgio M Bressan

Research output: Contribution to journalArticlepeer-review

Abstract

Objective- EMILIN-1 (elastin microfibrils interface located protein-1) protein inhibits pro-TGF-β (transforming growth factor-β) proteolysis and limits TGF-β bioavailability in vascular extracellular matrix. Emilin1-/- null mice display increased vascular TGF-β signaling and are hypertensive. Because EMILIN-1 is expressed in vessels from embryonic life to adulthood, we aimed at unravelling whether the hypertensive phenotype of Emilin1-/- null mice results from a developmental defect or lack of homeostatic role in the adult. Approach and Results- By using a conditional gene targeting inactivating EMILIN-1 in smooth muscle cells of adult mice, we show that increased blood pressure in mice with selective smooth muscle cell ablation of EMILIN-1 depends on enhanced myogenic tone. Mechanistically, we unveil that higher TGF-β signaling in smooth muscle cells stimulates HB-EGF (heparin-binding epidermal growth factor) expression and subsequent transactivation of EGFR (epidermal growth factor receptor). With increasing intraluminal pressure in resistance arteries, the cross talk established by TGF-β and EGFR signals recruits TRPC6 (TRP [transient receptor potential] classical type 6) and TRPM4 (TRP melastatin type 4) channels, lastly stimulating voltage-dependent calcium channels and potentiating myogenic tone. We found reduced EMILIN-1 and enhanced myogenic tone, dependent on increased TGF-β-EGFR signaling, in resistance arteries from hypertensive patients. Conclusions- Taken together, our findings implicate an unexpected role of the TGF-β-EGFR pathway in hypertension with current translational perspectives.

Original languageEnglish
Pages (from-to)2484-2497
Number of pages14
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume38
Issue number10
DOIs
Publication statusPublished - Oct 2018

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