期刊
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
卷 38, 期 10, 页码 2484-2497出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.118.311115
关键词
animals; calcium signaling; humans; mice; myocytes; smooth muscle
资金
- Fondazione Telethon [GGP06066]
- MIUR-PRIN (Ministero Istruzione Universita e Ricerca-Progetti di Ricerca di Interesse Nazionale) [2010RNXM9C_003]
- Italian Ministry of Health (Ricerca Corrente)
- MIUR-PRIN [2010RNXM9C_001]
- University of Padova [CPDR092325/09]
Objective EMILIN-1 (elastin microfibrils interface located protein-1) protein inhibits pro-TGF- (transforming growth factor-) proteolysis and limits TGF- bioavailability in vascular extracellular matrix. Emilin1(-/-) null mice display increased vascular TGF- 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- 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- 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--EGFR signaling, in resistance arteries from hypertensive patients. Conclusions Taken together, our findings implicate an unexpected role of the TGF--EGFR pathway in hypertension with current translational perspectives.
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