NYMC Faculty Publications
Angiotensin II Receptor Blockade or Deletion of Vascular Endothelial ACE Does Not Prevent Vascular Dysfunction and Remodeling in 20-HETE-Dependent Hypertension
Author Type(s)
Faculty
DOI
10.1152/ajpregu.00039.2015
Journal Title
American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
First Page
R71
Last Page
8
Document Type
Article
Publication Date
7-1-2015
Abstract
Increased vascular 20-HETE is associated with hypertension and activation of the renin-angiotensin system (RAS) through induction of vascular angiotensin-converting enzyme (ACE) expression. Cyp4a12tg mice, whose Cyp4a12-20-HETE synthase expression is under the control of a tetracycline (doxycycline, DOX) promoter, were used to assess the contribution of ACE/RAS to microvascular remodeling in 20-HETE-dependent hypertension. Treatment of Cyp4a12tg mice with DOX increased systolic blood pressure (SBP; 136 ± 2 vs. 102 ± 1 mmHg; P < 0.05), and this increase was prevented by administration of 20-HEDGE, lisinopril, or losartan. DOX-induced hypertension was associated with microvascular dysfunction and remodeling of preglomerular microvessels, which was prevented by 20-HEDGE, a 20-HETE antagonist, yet only lessened, but not prevented, by lisinopril or losartan. In ACE 3/3 mice, which lack vascular endothelial ACE, administration of 5α-dihydrotestosterone (DHT), a known inducer of 20-HETE production, increased SBP; however, the increase was about 50% of that in wild-type (WT) mice (151 ± 1 vs. 126 ± 1 mmHg). Losartan and 20-HEDGE prevented the DHT-induced increase in SBP in WT and ACE 3/3 mice. DHT treatment increased 20-HETE production and microvascular remodeling in WT and ACE 3/3 mice; however, remodeling was attenuated in the ACE 3/3 mice as opposed to WT mice (15.83 ± 1.11 vs. 22.17 ± 0.92 μm; P < 0.05). 20-HEDGE prevented microvascular remodeling in WT and ACE 3/3 mice, while losartan had no effect on microvascular remodeling in ACE 3/3. Taken together, these results suggest that RAS contributes to 20-HETE-mediated microvascular remodeling in hypertension and that 20-HETE-driven microvascular remodeling independent of blood pressure elevation does not fully rely on ACE activity in the vascular endothelium.
Recommended Citation
Garcia, V., Joseph, G., Shkolnik, B., Ding, Y., Zhang, F. F., Gotlinger, K., Falck, J. R., Dakarapu, R., Capdevila, J. H., Bernstein, K. E., & Schwartzman, M. L. (2015). Angiotensin II Receptor Blockade or Deletion of Vascular Endothelial ACE Does Not Prevent Vascular Dysfunction and Remodeling in 20-HETE-Dependent Hypertension. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology, 309 (1), R71-8. https://doi.org/10.1152/ajpregu.00039.2015