TY - JOUR
T1 - 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
AU - Carnevale, Daniela
AU - Facchinello, Nicola
AU - Iodice, Daniele
AU - Bizzotto, Dario
AU - Perrotta, Marialuisa
AU - De Stefani, Diego
AU - Pallante, Fabio
AU - Carnevale, Lorenzo
AU - Ricciardi, Franco
AU - Cifelli, Giuseppe
AU - Da Ros, Francesco
AU - Casaburo, Manuel
AU - Fardella, Stefania
AU - Bonaldo, Paolo
AU - Innocenzi, Gualtiero
AU - Rizzuto, Rosario
AU - Braghetta, Paola
AU - Lembo, Giuseppe
AU - Bressan, Giorgio M
PY - 2018/10
Y1 - 2018/10
N2 - 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.
AB - 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.
U2 - 10.1161/ATVBAHA.118.311115
DO - 10.1161/ATVBAHA.118.311115
M3 - Article
C2 - 30354220
VL - 38
SP - 2484
EP - 2497
JO - Arteriosclerosis, Thrombosis, and Vascular Biology
JF - Arteriosclerosis, Thrombosis, and Vascular Biology
SN - 1079-5642
IS - 10
ER -