| First Author | Pingili AK | Year | 2020 |
| Journal | Biol Sex Differ | Volume | 11 |
| Issue | 1 | Pages | 4 |
| PubMed ID | 31948482 | Mgi Jnum | J:297860 |
| Mgi Id | MGI:6479342 | Doi | 10.1186/s13293-019-0280-4 |
| Citation | Pingili AK, et al. (2020) 6beta-Hydroxytestosterone, a metabolite of testosterone generated by CYP1B1, contributes to vascular changes in angiotensin II-induced hypertension in male mice. Biol Sex Differ 11(1):4 |
| abstractText | BACKGROUND: Previously, we showed that 6beta-hydroxytestosterone (6beta-OHT), a cytochrome P450 1B1 (CYP1B1)-derived metabolite of testosterone, contributes to angiotensin II (Ang II)-induced hypertension in male mice. This study was conducted to test the hypothesis that 6beta-OHT contributes to increased vascular reactivity, endothelial dysfunction, vascular hypertrophy, and reactive oxygen species production associated with Ang II-induced hypertension. METHODS: Eight- to 10-week-old intact or castrated C57BL/6 J (Cyp1b1(+/+) and Cyp1b1(-/-)) mice were anesthetized for implantation of a micro-osmotic pump which delivered Ang II (700 ng/kg/day) or saline for 14 days. Mice were injected with 6beta-OHT (15 mug/g b.w every third day), flutamide (8 mg/kg every day), or its vehicle. Blood pressure was measured via tail-cuff. Vascular reactivity, endothelial-dependent and endothelial-independent vasodilation, media to lumen ratio, fibrosis by collagen deposition, and reactive oxygen species production by dihydroethidium staining were determined in the isolated thoracic aorta. RESULTS: The response of thoracic aorta to phenylephrine and endothelin-1 was increased in Ang II-infused Cyp1b1(+/+) mice compared to intact Cyp1b1(-/-) or castrated Cyp1b1(+/+) and Cyp1b1(-/-) mice; these effects of Ang II were restored by treatment with 6beta-OHT. Ang II infusion caused endothelial dysfunction, as indicated by decreased relaxation of the aorta to acetylcholine in Cyp1b1(+/+) but not Cyp1b1(-/-) or castrated Cyp1b1(+/+) and Cyp1b1(-/-) mice. 6beta-OHT did not alter Ang II-induced endothelial dysfunction in Cyp1b1(+/+) mice but restored it in Cyp1b1(-/-) or castrated Cyp1b1(+/+) and Cyp1b1(-/-) mice. Ang II infusion increased media to lumen ratio and caused fibrosis and reactive oxygen species production in the aorta of Cyp1b1(+/+) mice. These effects were minimized in the aorta of Cyp1b1(-/-) or castrated Cyp1b1(+/+) and Cyp1b1(-/-) mice and restored by treatment with 6beta-OHT. Treatment with the androgen receptor antagonist flutamide reduced blood pressure and vascular hypertrophy in castrated Ang II-infused mice injected with 6beta-OHT. CONCLUSIONS: 6beta-OHT is required for the action of Ang II to increase vascular reactivity and cause endothelial dysfunction, hypertrophy, and increase in oxygen radical production. The effect of 6beta-OHT in mediating Ang II-induced hypertension and associated hypertrophy is dependent on the androgen receptor. Therefore, CYP1B1 could serve as a novel target for the development of therapeutics to treat vascular changes in hypertensive males. |
