Recently we showed that 2-methoxyestradiol (2-ME), an estrogen (E2) metabolite generated by CYP1B1 (cytochrome P450 1B1) in the paraventricular nucleus (PVN), protects female mice from Ang (angiotensin) II-induced hypertension and increased renal sympathetic activity. We also demonstrated that group IV cPLA
2
α (cytosolic phospholipase A
2
α) in the brain contributes to Ang II-induced hypertension in male mice. This study was conducted to determine the contribution of central cPLA
2
α and its relationship to CYP1B1 in Ang II-induced hypertension in female mice. cPLA
2
α knockdown in the PVN by transduction with adenovirus (Ad)-cPLA
2
α-short hairpin (sh)RNA (200 nL, bilaterally, 1.0х10
12
pfu/mL) but not its control Ad-scrambled (Scr)-shRNA (2.5х10
11
pfu/mL) in ovariectomized (OVX) wild-type (
cPLA
2
α
+/+
/
Cyp1b1
+/+
, n=8/group) and intact
cPLA
2
α
+/+
/
Cyp1b1
-/-
(n=12/group) female mice attenuated the effect of Ang II (700 ng/kg/min, subcutaneous, osmotic pump, 2 weeks) to increase the systolic blood pressure (SBP, mmHg) as measured by tail-cuff (Day 12: 129±3 vs 168±7 and 119±3 vs 172±5, respectively, P<0.05). Moreover, reconstitution of cPLA
2
α in the PVN by transduction with Ad-cPLA
2
α-DNA (1.1х10
12
pfu/mL) but not its control Ad-GFP-DNA (1.0х10
11
pfu/mL) in OVX-
cPLA
2
α
-/-
/
Cyp1b1
+/+
mice (n=4/group) restored the effect of Ang II to increase SBP (Day 12: 163±7 vs 124±4, P<0.05). Furthermore, Ad-cPLA
2
α-shRNA but not Ad-Scr-shRNA transduction in the PVN in OVX-
cPLA
2
α
+/+
/
Cyp1b1
+/+
and intact
cPLA
2
α
+/+
/
Cyp1b1
-/-
mice reduced and Ad-cPLA
2
α-DNA but not Ad-GFP-DNA transduction in the PVN in OVX-
cPLA
2
α
-/-
/
Cyp1b1
+/+
mice restored the effect of Ang II to increase the renal sympathetic activity as indicated by urinary norepinephrine level (ng/mL, 324±36 vs 707±94, 359±49 vs 979±70, 690±44 vs 421±43, respectively, n=4/group, P<0.05) and proteinuria (mg/24 hour, 4±1 vs 10±0.4, 3±0.4 vs 7±1, 9±0.8 vs 3±0.7, respectively, n=4/group, P<0.05). These data suggest that E2-CYP1B1 derived metabolite 2-ME protects against Ang II-induced hypertension, renal sympathetic activity, and proteinuria by inhibiting cPLA
2
α activity in the PVN. Thus, 2-ME and/or agents inhibiting cPLA
2
α activity could be useful for treating hypertension and its pathogenesis in females.
Faculty Opinions recommendation of Phosducin influences sympathetic activity and prevents stress-induced hypertension in humans and mice.