Abstract 13748: A Disintegrin and Metalloproteinase 17 Deletion in Smooth Muscle Cell Transiently Suppresses Angiotensin II Mediated Hypertension
Introduction: A disintegrin and metalloproteinase-17 (ADAM17) proteolytically releases membrane-bound growth factors and cytokines. Hypertension is associated with remodeling, hypertrophy and hyperplasia of smooth muscle cells (SMCs). ADAM17 has been reported to mediate Angiotensin II (Ang II)-induced SMC hypertrophy. We investigated the role of smooth muscle cell ADAM17 in Ang II-induced hypertension.
Hypothesis: Smooth muscle cell ADAM17 deficiency suppresses Ang II-induced hypertension.
Methods: SMC-specific ADAM17-deficient mice (Adam17flx/flx/SM22Cre; Adam17SMC-Cre), and littermate controls (Adam17flx/flx) received Ang II or saline (Alzet pumps, 1.5 mg/kg/d; 4 wks). Blood pressure was measured in conscious mice before and 4 wks after Ang II infusion (Telemetry). Vascular function (vasoconstrictor/dilator response), circumferential wall stress/strain were assessed in second order mesenteric arteries ex vivo at 2 wks after Ang II/saline infusion.
SMCs were isolated from either genotype (enzyme dispersal method). SMC proliferation (BrdU incorporation), migration (scratch assay) and apoptosis (Annexin V/7-AAD staining, Flow Cytometry) were assessed (±Ang II). Activation of signaling pathways (phospho/total EGFR, Akt and ERK1/2), HB-EGF were assessed by Western blot.
Results: Adam17SMC-Cre mice exhibited suppressed hypertension in the 1st week of Ang II infusion (reduced systolic, diastolic & MAP). However, by the 2nd week, systolic and diastolic BP rose to similar levels as Adam17flx/flx mice and remained similar. Ex vivo analyses revealed similar acute vasoconstrictor/dilator responses, and comparable wall stiffness in both genotypes; but the Ang II-induced increase in wall thickness was not observed in Adam17SMC-Cre group.
ADAM17-deficient SMCs showed reduced Ang II-induced proliferation, migration, and activation of HB-EGF and ERK1/2. A time-course study revealed delayed Ang II-mediated EGFR activation in ADAM17-deficient SMCs (@24 hrs vs 30 min).
End organ damage, hypertrophy and fibrosis in the heart and kidneys, were comparable.
Conclusions: ADAM17 deficiency in SMCs causes a transient reduction in Ang II-induced hypertensive response, possibly due to delayed activation of the EGFR pathway.
Author Disclosures: M. Shen: None. J. Morton: None. S.T. Davidge: None. Z. Kassiri: None.
- © 2016 by American Heart Association, Inc.