In:
Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 38, No. 10 ( 2018-10), p. 2484-2497
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
1079-5642
,
1524-4636
DOI:
10.1161/ATVBAHA.118.311115
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2018
detail.hit.zdb_id:
1494427-3
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