Vascular dysfunction and remodeling associated with 20‐HETE‐dependent hypertension is prevented in 20‐HETE receptor (GPR75) null mice

Abstract

The potent vasoactive lipid 20‐Hydroxyeicosatetraenoic acid (20‐HETE) exhibits a range of bioactions across the vasculature including stimulation of endothelial dysfunction (ED) and increases in smooth muscle contractility; all of which promote hypertension. We have recently identified the G‐protein coupled receptor 75 (GPR75) as the receptor to which 20‐HETE binds and triggers signaling pathways culminating with the aforementioned effects. Previous studies have clearly shown the Cyp4a12tg mouse to be an animal model for the study of 20‐HETE and phenotypes associated with 20‐HETE‐dependent hypertension. In this model, expression of the 20‐HETE synthase, Cyp4a12, is under the control of a tetracycline (doxycycline, DOX) promoter and treatment of Cyp4a12tg (Gpr75+/+4a12tg) mice with DOX elicits increases circulating 20‐HETE levels followed by the promotion of pro‐hypertensive signaling including decreases in nitric oxide (NO) production and increases in vascular angiotensin converting enzyme (ACE) resulting in elevations in blood pressure (BP) (136 ± 4 vs. 103 ± 4 mmHg; P < 0.05). In this study, we examined whether the deletion of GPR75 affects the onset and progression of hypertension and vascular remodeling in the Cyp4a12tg mice by crossing Gpr75−/− with Cyp4a12tg mice. Gpr75−/− 4a12tg treated with DOX chow for 42 days did not exhibit any changes in BP (103 ± 4 vs. 100 ± 6 mmHg). 20‐HETE‐mediated increases in BP in DOX‐treated Cyp4a12tg mice are associated with ED as indicated by reduced relaxation response to acetylcholine (ACh). Wire myography of renal interlobar arteries from DOX‐treated Gpr75+/+4a12tg mice pre‐constricted with phenylephrine exhibited a diminished relaxation response to ACh compared to mice receiving regular chow (44 ± 4% vs. 91 ± 2% relaxation; P < 0.05). In contrast, ACh‐induced relaxations in arteries from DOX‐treated Gpr75−/− 4a12tg mice were not impaired and responded similarly to ACh as vessels from vehicle‐treated Gpr75−/− 4a12tg mice (89 ± 1% vs. 89 ± 2% relaxation; P < 0.05). Another hallmark of persistent elevations in BP over time and 20‐HETE‐dependent hypertension is the development of dynamic vascular remodeling with increases in media thickness (MT), media‐to‐lumen ratio (M:L) and cross sectional area (CSA). Gpr75+/+4a12tg mice receiving DOX for 42 days exhibit an increase in remodeling of renal resistance arteries as indicated by elevations in MT (24 ± 1 vs. 12 ± 1 μm), M:L (0.29 ± 0.02 vs. 0.12 ± 0.01) and CSA (15 ± 1 vs. 8 ± 1 μm2 × 103) compared to Gpr75+/+4a12tg mice receiving regular chow. In contrast, DOX treated Gpr75−/− 4a12tg mice, as opposed to vehicle‐treated Gpr75−/− 4a12tg mice, did not display any changes to MT (12 ± 1 vs. 11 ± 1 μm), M:L (0.13 ± 0.01 vs. 0.11 ± 0.01 ) or CSA (8± 1 vs. 7 ± 0.3 μm2 × 103). Taken together, this data support the hypothesis that 20‐HETE required its receptor, GPR75, in order to drive pro‐hypertensive signaling that promotes endothelial dysfunction, vascular remodeling and hypertension.Support or Funding InformationSupported by NIH grants HL39793 (MLS), HL39793‐01S1 (VG) and by the Intramural Research Program of the NIH (Z01 ES025034 (DCZ)).