Table 5.
Major animal studies of E2 or estrogen metabolites in PH.
| Model | Species | Major findings | References |
|---|---|---|---|
| Isolated lungs or isolated PAs | Rat, sheep | Female sex, high estrogen states (pregnancy, proestrus), exogenous E2 or selective ERα or ERβ agonist ↓ HPV and/or drug-induced PA vasocontraction | (116, 208-210, 214, 335, 473) |
| Hypoxia-induced PH (HPH) | Rat, chicken, swine, mouse | Females protected; OVX ↑ PH, E2 replacement in OVX ↓ PH |
(42, 92, 267, 327, 335) |
| E2 administration ↓ HPH in male rats | (208, 474) | ||
| E2 ↓ ET-1, ERK1/2, Akt, Skp2 | (92, 208, 474) | ||
| E2 ↑ p27Ki1, LC3B | (208, 474) | ||
| ERα and ERβ ↓ pro-proliferative signaling | (208) | ||
| ER-mediated anti-proliferative E2 effects on PAECs | (208) | ||
| ↓ proliferation in hypoxic PASMCs from proestrus rats | (463) | ||
| CYP1B1 ↑ in male and female mice; inhibition protective; knockout ↓ PH and PA remodeling in male mice only |
(473) | ||
| 16α-OHE1 ↑ in HPH; treatment of HPH mice with 16α-OHE1 ↑ PH | (463) | ||
| Hypoxia ↑ ERβ in rat lungs and cultured PAEC from rats and humans; ERβ ↓ HIF-activation and proliferative processes in PAECs and HPH lungs | (115) | ||
| E2 regulates proliferative and inflammatory gene expression via ER during hypoxia; E2 ↓ gremlin expression and ↑ BMPR2 signaling in hypoxic lungs | (112) | ||
| Aromatase inhibition ↓ PH in hypoxic female mice | (248) | ||
| Monocrotaline-induced PH (MCT-PH) | Rat | Females protected; OVX ↑ PH, 2ME2 replacement in OVX ↓ PH E2 metabolites (2OHE2, 2ME2, 2EE) protective E2 pro-angiogenic and anti-inflammatory |
(421, 432, 483) (418, 420, 421, 423) (432) |
| ERβ-mediated protection | (432) | ||
| MCT-PH “estrogen-deficient” state (↓ lung aromatase, lung ERa, plasma E2, ↑ CYP1B1) | (483) | ||
| E2 ↓ ET-1, ↑ NO, ↑ PGI2 | (483) | ||
| Activation of nongenomic ER (GPR30) in male or OVX female MCT rats: ↓ RVH, ↓ RVSP, ↑ exercise endurance | (5, 6) | ||
| E2 treatment ↓ RVSP, ↓ RVH, ↓ pulmonary vascular remodeling after MCT injection of aged ApoE~−/− mice | (433) | ||
| Phytoestrogen genistein ↓ MCT-PH by ↓ miR206 and ↑ pulmonary angiogenesis | (260, 366) | ||
| Sugen/hypoxia-induced PH | Rat, mouse | Only mild hemodynamic alterations in female rats CYP1B1 ↑ in male and female mice; CYP1B1 inhibition ↓ PH |
(348) (463) |
| E2 protective in OVX SuHx rats ↓ RVSP, ↓ PA muscularization, ↓ RVH, ↑ CI, ↑ VO2max ERα agonist replicates E2 effects | (114) | ||
| E2 administration in males: ↓ RVH, ↓ apoptotic signaling, ↑ apelin | (114) | ||
| E2 ↑ RV adaptation after acute exercise in SuHx-PH rats | (213) | ||
| E2 treatment in SuHx-PH OVX mice: ↓ RV afterload, ↓ PA muscularization, ↑ PA compliance, ↑ RVEF, ↑ CO, maintains pulmonary hemodynamics | (232, 234, 235) | ||
| E2 treatment preserves RV mitochondria number and function in OVX rats | (233) | ||
| SuHx-PH ↑ CYP1A1, ↑ aromatase. Inhibition of aryl hydrocarbon receptor (AhR) reversed this effect | (70) | ||
| Aromatase inhibition ↓ PH in female rats | (248) | ||
| Serotonin transporter overexpression (SERT+) |
Mouse | Female mice develop ↑ PA pressure at normoxia and ↑ PH during hypoxia exposure; OVX protective; E2 detrimental | (462) |
| E2 ↑ proliferation, Tph-1, 5-HT1B receptor, and SERT expression in human PASMCs | (462) | ||
| CEBPβ, FOS, CYP1B1 ↑ in female hypoxic SERT+ mice; E2 ↑ these factors in human PASMCs | (464) | ||
| SERT+ mice overexpress CYP1B1; CYP1B1 inhibition prevents spontaneous PH phenotype | (179) | ||
| S100A4/Mts1 overexpression |
Mouse | Female MTS1+ mice more susceptible to PH development than males: ↑ RVSP, ↑ pulmonary vascular remodeling in females | (72) |
| E2 treatment ↑ Mts1 and ↑ proliferation in hPASMCs in a RAGE-dependent manner | (72) | ||
| Dexfenfluramine (Dfen)-induced PH |
Mouse | Only females develop PH; OVX protective CYP1B1 necessary for PAH development in Dfen-treated mice |
(71) (71) |
| Dfen and E2 treatments ↑ CYP1B1 and Tph1 expression in cultured PAH-PASMCs |
(71) | ||
| BMPR2 mutation- induced PH | Mouse | 16α-OHE1 ↑ disease penetrance and ↑ RV dysfunction 16α-OHE1 ↓ BMPR2 signaling in control mice but not in BMPR2 mutants |
(101) (101) |
| 16α-OHE1 ↓ cytokine expression but ↑ alterations in genes related to platelet function, angiogenesis, Wnt pathway, and energy metabolism | (101) | ||
| Lack of protective effect of 2-ME2 | (101) | ||
| Altered intracellular localization of ERα in BMPR2 mutant pulmonary microvascular endothelial cells (associated with insensitivity to activation by E2) | (101) | ||
| Estrogen inhibition ↓ PH | (51) | ||
| 16α-OHE1 ↑ PH via upregulation of microRNA-29 (miR-29) | (52) |
Studies organized by model system. 16α-OHE1, 16-alpha hydroxyestrone; 2EE, 2-ethoxyestradiol; 2ME2, 2-methoxyestradiol, Akt, RAC-alpha serine/threonine-protein kinase; ApoE, apolipoprotein E; Bmpr2, bone morphogenetic protein receptor 2; CEBPβ, CCAAT enhancer binding protein beta; CI, cardiac index; CO, cardiac output; CYP1B1, cytochrome P450 1 subfamily B member 1; ERK1, extracellular signal-regulated kinase 1; ET1, endothelin 1; FOS, Fos proto-oncogene, AP-1 transcription factor subunit; eNOS, endothelial nitric oxide synthase; HIF, hypoxia-inducible factor; HPH, hypoxia-induced pulmonary hypertension; HPV, hypoxic pulmonary vasoconstriction; LC3B, autophagy-related ubiquitin-like modifier LC3 B; MCT, monocrotaline; NO, nitric oxide; OVX, ovariectomy; P27Kip1, cyclin-dependent kinase inhibitor 1B; PGI2, prostacyclin; RAGE, receptor for advanced glycation end products; RVEF, right ventricular ejection fraction, RVH, right ventricular hypertrophy, SERT+, serotonin transporter over-expression; SKP2, S-phase kinase-associated protein 2; SuHx, sugen-hypoxia; Tph1, tryptophan hydroxylase 1; VO2max, maximal oxygen uptake.