Abstract 342: Vascular Endothelial Ace Deletion Or AT1R Blockade Reduces Blood Pressure But Does Not Prevent Vascular Remodeling In Models Of 20-HETE-Dependent Hypertension
20-HETE-mediated hypertension in rats and mice is associated with increased vascular ACE expression and Ang II levels. We examined the contribution of vascular ACE to blood pressure (BP) and vascular remodeling in 20-HETE-dependent hypertension. The ACE3/3 mice lack vascular endothelial ACE, exhibit attenuated renal ACE expression and display normal plasma ACE and Ang II levels. Administration of 5α-dihydrotestosterone (DHT) (100 mg; 21-day pellet), an inducer of 20-HETE production, increased systolic BP (SBP) by 50% in WT mice (148±4 vs 99±2 mmHg) and 26% in ACE 3/3 mice (125±1 vs 99±1 mmHg). Administration of losartan (10 mg/kg/day) or 20-HEDGE (20-HETE antagonist, 10mg/kg/day) at day 14 of DHT treatment reduced SBP in WT and ACE3/3 mice to levels of untreated mice. DHT increased ACE protein in WT by 2.3-fold in mesenteric and 2.6-fold in aortic arteries while ACE3/3 mice lacked vascular ACE expression which remained absent under DHT treatment. DHT increased preglomerular microvessel (PGMV) remodeling in WT and ACE3/3 mice; however, remodeling was attenuated in ACE3/3 mice (media thickness, 14.54±1.24 vs 9.80±0.56 μm; p<0.05) as opposed to WT mice (22.17±0.92 vs 9.68±0.76 μm; p<0.05). In Cyp4a12tg mice, in which the expression of the Cyp4a12-20-HETE synthase is under the control of the doxycycline (DOX) promoter, DOX (1 mg/ml drinking water) increased SBP (136±2 vs 102±1 mmHg; p<0.05). The increase in SBP was prevented by co-treatment with 20-HEDGE (103±3mmHg), lisinopril (100±3mmHg), or losartan (102±3mmHg). DOX treatment increased PGMV remodeling when compared to untreated Cyp4a12tg mice (media thickness, 16.1±0.9 vs. 8.2±0.5 μm, p<0.05). Co-treatment with 20-HEDGE (10 mg/kg/day) prevented DOX-induced PGMV remodeling (8.8±0.6 μm, p<0.05) while co-treatment with lisinopril or losartan attenuated but did not prevent PGMV remodeling (12.0±0.5 and 11.1±0.5 μm). DOX-treated Cyp4a12tg displayed increased ACE expression in PGMV which was negated by treatment with 20-HEDGE but unaffected by either losartan or lisinopril treatment. These results suggest that vascular endothelial ACE contributes, in part, to 20-HETE-mediated microvascular remodeling in hypertension and that 20-HETE have effects on microvascular remodeling independent of RAS.
Author Disclosures: G. Joseph: None. V. Garcia: None. E. Steadman: None. Y. Ding: None. B. Shkolnik: None. J. Capdevila: None. J.R. Falck: None. K.E. Bernstein: None. M.L. Schwartzman: None.
- © 2014 by American Heart Association, Inc.