20‐HETE INDUCES REMODELING OF RENAL RESISTANCE ARTERIES INDEPENDENT OF BLOOD PRESSURE ELEVATION IN ANDROGEN‐INDUCED HYPERTENSION

Abstract

20‐Hydroxyeicosatetraenoic acid (20‐HETE) is a cytochrome P450‐derived arachidonate metabolite that has been shown to increase smooth muscle contractions and proliferation, stimulate endothelial dysfunction and promote hypertension. We examined if 20‐HETE contributes to vascular remodeling in androgen‐induced hypertension. In Sprague‐Dawley (SD) rats treated with 5α‐dihydrotestosterone (DHT), the increase in blood pressure (BP) is prevented by 20‐HETE inhibitor, HET0016, or 20‐HETE antagonist, 20–6,15‐HEDE. Likewise, inhibition of 20‐HETE's biosynthesis or activity abrogated DHT‐induced remodeling in renal interlobar arteries. In cyp4a14−/− mice, which display androgen‐driven and 20‐HETE‐dependent hypertension, treatment with 20–6,15‐HEDE abolished remodeling of renal interlobar arteries decreasing media thickness from 23.67±0.88 to 14.56±0.59μm and M/L from 0.29±0.03 to 0.17±0.01. To assess whether 20‐HETE induces vascular remodeling independent of BP increase, SD rats were administered reserpine (100μg/kg/day) and DHT for 21 days. Reserpine prevented BP elevation but did not affect vascular remodeling; under these conditions, treatment with 20–6,15‐HEDE attenuated vascular remodeling. This study demonstrates that 20‐HETE is a key regulator of vascular remodeling in androgen‐induced hypertension; its effect is independent of BP elevation.