Potential vascular actions of 2-methoxyestradiol

Abstract

2-Methoxyestradiol (2-ME) is a biologically active metabolite of 17beta-estradiol that appears to inhibit key processes associated with cell replication in vitro. The molecule has been suggested to have potent growth-inhibitory effects on proliferating cells, including smooth muscle cells and endothelial cells, and may be antiangiogenic. Because of these potential roles for 2-ME, its lack of cytotoxicity and low estrogenic activity, we hypothesize that 2-ME could be a valuable therapeutic molecule for prevention and treatment of cardiovascular diseases. Whether 2-ME is as effective in vivo as it is in vitro at modulating vascular processes remains controversial. Here we discuss recent developments regarding mechanisms by which 2-ME might regulate vascular activity and angiogenesis and speculate on the therapeutic implications of these developments.

Figure 1

The endogenous formation and metabolism of 17β-estradiol (E2). (a) E2 interacts with ERα and ERβ to mediate its estrogenic actions in multiple tissues; (b) Endogenous E2 is metabolized to 2-hydroxyestradiol (2-HE) and 2-methoxyestradiol (2-ME) via the sequential actions of cytochrome P450 (CYP) and catechol-O-methyltransferase (COMT). CYP exists in multiple isoforms that are capable of metabolizing estradiol to catecholestradiols (e.g., CYP1A1, CYP1A2, CYP1B1 and CYP3A4). 2-HE has mild estrogenic actions and is rapidly metabolized to 2-ME. 2-ME has little or no affinity for ERs and mediates its biologic actions via ER-independent mechanisms. (c) 2-ME is rapidly cleared from the body via phase II conjugation enzymes involving glucuronidation and sulfation (hepatic clearance: 712 ml/min in humans). Moreover, demethylation can reconvert 2-ME to 2-HE. ER, estrogen receptor.

Figure 2

The potential beneficial effects of 2-methoxyestradiol (2-ME) are shown. 2-ME induces cardiovascular protection and attenuates pulmonary hypertension by improving endothelial function and inhibiting abnormal growth of vascular smooth muscle cells (VSMCs), synthesis of extracellular matrix (ECM) proteins like collagen, infiltration of inflammatory cells (monocytes/macrophages) in vascular lesions and lowering cholesterol levels. Similar to VSMCs, 2-ME inhibits left ventricular hypertrophy by inhibiting abnormal growth and ECM synthesis/deposition by cardiac fibroblasts (CF). 2-ME reduces cardiovascular and renal damage associated with the metabolic syndrome and obesity. 2-ME may also protect against renal disease/toxicity by attenuating glomerulosclerosis/glomerular remodeling by inhibiting the abnormal growth of glomerular mesangial cells (GMC), deposition of EMC proteins like collagen by GMCs and infiltration of inflammatory cells (monocytes/macrophages). ↑ induction; ↓ inhibition.

Figure 3

Schematic representation of the cellular mechanisms in vascular smooth muscle cells (VSMCs) via which 2-methoxyestradiol (2-ME) potentially inhibits proliferation, migration and extracellular matrix (ECM) synthesis and mediates anti-vasoocclusive actions. 2-methoxyestradiol, 2-ME; positive cell cycle regulators include phosphorylated mitogen activated kinase, hyperphosphorlyated retinoblastoma protein, phosphorylated-Akt, cyclin D₁, cyclin B₁; negative regulators of cell cycle include p27; HIF-1α, hypoxia-induced factor-1α; ↓, inhibition; ↑, activation, ? unknown.

Figure 4

Schematic representation of the cellular mechanisms in endothelial cells mediating the antiangiogenic and capillary barrier actions of 2-ME. (i) Disruption of tubulin dynamics by 2-ME inhibits cellular accumulation of hypoxia-induced factor-1α (HIF-1α), thereby inhibiting its translocation to the nucleus and resulting in inhibition of transcription and secretion of angiogenic factors like vascular endothelial growth factor-1 (VEGF-1). Decreased generation of VEGF-1 and Fms-like tyrosine kinase-1 (sFLT-1) protects against endothelial cell proliferation, migration and survival as well as endothelial barrier dysfunction. 2-ME can also induce antiangiogenic effects by causing endothelial cell apoptosis. (ii) 2-ME can generate reactive oxygen species (ROS) via activating c-Jun N-terminal kinase (JNK) or directly interacting with mitochondria to stimulate caspase-3 leading to apoptosis. (iii) 2-ME can also trigger apoptosis by upregulating the extrinsic pathway by increasing the expression of death receptor (DR5) and activating caspase-8. The collective effects of these mechanisms are protection against endothelial barrier disruption and capillary leak, inhibition of angiogenic activity and neovascularisation, and potential protection against tumor progression, plaque development, pulmonary hypertension, obesity, pre-eclampsia, renal disease, eye disease, endometriosis and rheumatoid arthritis. ↓, inhibition; ↑, increase; ------- hypothesized effects.