Angiotensin II receptor blockade or deletion of vascular endothelial ACE does not prevent vascular dysfunction and remodeling in 20-HETE-dependent hypertension.
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.
Department of Pharmacology, New York Medical College, Valhalla, New York; Victor_Garcia@nymc.edu.
Victor
V
Garcia
Department of Pharmacology, New York Medical College, Valhalla, New York;
Gregory
G
Joseph
Department of Pharmacology, New York Medical College, Valhalla, New York;
Brian
B
Shkolnik
Department of Pharmacology, New York Medical College, Valhalla, New York;
Yan
Y
Ding
Department of Pharmacology, New York Medical College, Valhalla, New York;
Frank Fan
FF
Zhang
Department of Pharmacology, New York Medical College, Valhalla, New York;
Katherine
K
Gotlinger
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas;
John R
JR
Falck
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas;
Rambabu
R
Dakarapu
Departments of Medicine and Biochemistry, Vanderbilt University, Nashville, Tennessee; and.
Jorge H
JH
Capdevila
Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California.
Kenneth E
KE
Bernstein
Department of Pharmacology, New York Medical College, Valhalla, New York;
Michal Laniado
ML
Schwartzman
D000804:Angiotensin II / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D013196:Dihydrotestosterone; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D005260:Female; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism*; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D008297:Male; D008822:Mice, Transgenic; D055806:Microvessels / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D007703:Peptidyl-Dipeptidase A / Q000172:deficiency* / Q000235:genetics; D012084:Renin-Angiotensin System / Q000187:drug effects; D013997:Time Factors; D066253:Vascular Remodeling / Q000187:drug effects*
D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D006893:Hydroxyeicosatetraenoic Acids; D013196:Dihydrotestosterone; D000804:Angiotensin II; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D003577:Cytochrome P-450 Enzyme System; D007703:Peptidyl-Dipeptidase A
20-HETE; ACE; angiotensin II; angiotensin-converting enzyme; hypertension; vascular remodeling