| First Author | Carnevale D | Year | 2018 |
| Journal | Arterioscler Thromb Vasc Biol | Volume | 38 |
| Issue | 10 | Pages | 2484-2497 |
| PubMed ID | 30354220 | Mgi Jnum | J:285069 |
| Mgi Id | MGI:6385399 | Doi | 10.1161/ATVBAHA.118.311115 |
| Citation | Carnevale D, et al. (2018) Loss of EMILIN-1 Enhances Arteriolar Myogenic Tone Through TGF-beta (Transforming Growth Factor-beta)-Dependent Transactivation of EGFR (Epidermal Growth Factor Receptor) and Is Relevant for Hypertension in Mice and Humans. Arterioscler Thromb Vasc Biol 38(10):2484-2497 |
| abstractText | Objective- EMILIN-1 (elastin microfibrils interface located protein-1) protein inhibits pro-TGF-beta (transforming growth factor-beta) proteolysis and limits TGF-beta bioavailability in vascular extracellular matrix. Emilin1(-/-) null mice display increased vascular TGF-beta 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-beta 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-beta 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-beta-EGFR signaling, in resistance arteries from hypertensive patients. Conclusions- Taken together, our findings implicate an unexpected role of the TGF-beta-EGFR pathway in hypertension with current translational perspectives. |
