Abstract
20-Hydroxyeicosatetraenoic acid (20-HETE) promotes smooth muscle contraction and proliferation, endothelial dysfunction and activation and hypertension. We have previously demonstrated that 20-HETE mediates androgen-induced hypertension. This study examines if 20-HETE contributes to vascular remodeling in androgen-induced hypertension. Sprague-Dawley rats were treated with vehicle or 5α-dihydrotestosterone (DHT) with and without the 20-HETE synthesis inhibitor (HET0016, 10mg/kg/day) for 14 days. Media-to-lumen ratio (M:L) in renal interlobar arteries from DHT-treated rats was higher (P<0.05) than vehicle-treated rats (0.21±0.01 vs. 0.15±0.02). This was prevented by HET0016 (0.14±0.01). Arteries from DHT-treated rats had increased (p<0.05) collagen type IV that was attenuated by HET0016. To assess whether 20-HETE induces vascular remodeling independent of blood pressure (BP) increase, reserpine (100 μg/kg/day) was administered to DHT- and vehicle-treated rats for 21 days. DHT increased BP (133.7±2.4 vs. 101.40±0.40 mmHg). Reserpine prevented this BP increase (104.20±1.30 mmHg) but had no effect on DHT-induced increase in M:L ratio (0.19±0.02) or in collagen I/IV deposition. These results suggest that DHT-mediated vascular remodeling is 20-HETE-dependent and that 20-HETE may contribute to DHT-induced vascular remodeling independent of BP elevation. Whether 20-HETE induces vascular remodeling in a DHT-independent manner was also examined. Cyp4a12 transgenic mice were treated with doxycycline (DOX) for 42 days to upregulate the cyp4a12 expression. BP of DOX-treated cyp4a12tg mice significantly increased compared to vehicle (139.59±4.06 vs. 92.25±5.25 mmHg) and 20-6,15-HEDE abolished BP increase (88.63±1.13 mmHg). Media thickness and M:L ratio significantly increased in DOX-treated group compared to vehicle (23.40±1.15 vs. 16.25±0.83μm; 0.39±0.04 vs. 0.23±0.02) and decreased by co-treatment with 20-6,15-HEDE (18.42±1.53μm; 0.28±0.03). These results indicate that 20-HETE can induce vascular remodeling in the absence of androgen.
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