Blockade of 20-Hydroxyeicosatetraenoic Acid Receptor Lowers Blood Pressure and Alters Vascular Function in Mice With Smooth Muscle-Specific Overexpression of CYP4A12-20-HETE Synthase

Authors

Kevin Agostinucci, Department of Pharmacology, New York Medical College School of Medicine, Valhalla, New York.Follow
Rebecca Hutcheson, Department of Pharmacology, New York Medical College School of Medicine, Valhalla, New York.
Sakib Hossain, Department of Pharmacology, New York Medical College School of Medicine, Valhalla, New York.
Jonathan V. Pascale, Department of Pharmacology, New York Medical College School of Medicine, Valhalla, New York.
Elizabeth Villegas, Department of Pharmacology, New York Medical College School of Medicine, Valhalla, New York.
Frank Zhang, Department of Pharmacology, New York Medical College School of Medicine, Valhalla, New York.
Adeniyi Michael Adebesin, Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
John R. Falck, Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Sachin Gupte, Department of Pharmacology, New York Medical College School of Medicine, Valhalla, New York.
Victor Garcia, Department of Pharmacology, New York Medical College School of Medicine, Valhalla, New York.
Michal Laniado Schwartzman, Department of Pharmacology, New York Medical College School of Medicine, Valhalla, New York.

Author Type(s)

Faculty

Journal Title

Journal of Hypertension

First Page

498

Last Page

511

Document Type

Article

Publication Date

3-1-2022

Department

Pharmacology

Abstract

OBJECTIVE: 20-Hydroxyeicosatetraenoic acid (20-HETE) is a vasoactive eicosanoid exhibiting effects on vascular smooth muscle cell (VSMC) via G-protein coupled receptor 75 (GPR75) and include stimulation of contractility, migration, and growth. We examined whether VSMC-targeted overexpression of CYP4A12, the primary 20-HETE-producing enzyme in mice, is sufficient to promote hypertension. METHODS: Mice with VSM-specific Cyp4a12 overexpression (Myh11-4a12) and their littermate controls (WT) were generated by crossbreeding Cyp4a12-floxed with Myh11-Cre mice. The 20-HETE receptor blocker, N-disodium succinate-20-hydroxyeicosa-6(Z),15(Z)-diencarboxamide (AAA), was administered in the drinking water. Experiments were carried out for 12 days. SBP was measured by tail cuff. Renal interlobar and mesenteric arteries were harvested for assessment of gene expression, 20-HETE levels, vascular contractility, vasodilation, and remodeling. RESULTS: Vascular and circulatory levels of 20-HETE were several folds higher in Myh11-4a12 mice compared with WT. The Myh11-4a12 mice compared with WT were hypertensive (145 ± 2 vs. 127 ± 2 mmHg; P < 0.05) and their vasculature displayed a contractile phenotype exemplified by increased contractility, reduced vasodilatory capacity, and increased media to lumen ratio. All these features were reversed by the administration of AAA. The mechanism of increased contractility includes, at least in part, Rho-kinase activation followed by increased myosin light chain phosphorylation and activation of the contractile apparatus. CONCLUSION: VSM-specific Cyp4a12 overexpression is sufficient to alter VSM cell phenotype through changes in contractile markers and enhancement in contractility that promote hypertension and vascular dysfunction in a 20-HETE-dependent manner. The 20-HETE receptor GPR75 may represent a novel target for the treatment of hypertension and associated vascular conditions.

Recommended Citation

Agostinucci, K., Hutcheson, R., Hossain, S., Pascale, J. V., Villegas, E., Zhang, F., Adebesin, A. M., Falck, J. R., Gupte, S., Garcia, V., & Schwartzman, M. L. (2022). Blockade of 20-Hydroxyeicosatetraenoic Acid Receptor Lowers Blood Pressure and Alters Vascular Function in Mice With Smooth Muscle-Specific Overexpression of CYP4A12-20-HETE Synthase. Journal of Hypertension, 40 (3), 498-511. https://doi.org/10.1097/HJH.0000000000003038