Endometriosis-Associated Angiogenesis and Anti-angiogenic Therapy for Endometriosis

Abstract

Endometriosis is a known estrogen-dependent inflammatory disease affecting reproductive-aged women. Common symptoms include pelvic pain, dysmenorrhea, dyspareunia, heavy menstrual bleeding, and infertility. The exact etiology of endometriosis is largely unknown, and, thus, the diagnosis and treatment of endometriosis are challenging. A complex interplay of many molecular mechanisms is thought to aid in the progression of endometriosis, most notably angiogenesis. This mini-review examines our current knowledge of the molecular etiology of endometriosis-associated angiogenesis and discusses anti-angiogenic therapy, in the blockade of endometriosis-associated angiogenesis, as potential non-hormonal therapy for the treatment of endometriosis.

Keywords: angiogenesis; anti-angiogenic therapy; endometriosis; estrogen receptors; vascular endothelial growth factor.

Figure 1

Schematic diagram of VEGF expression by Estradiol (E2) and Estrogen Receptors (ERs) through the Wnt/β-catenin signaling pathway. E2 promotes the direct binding of ERα to the Estrogen Response Element (ERE) site of the β-catenin promotor, enhancing its expression (45). E2 also activates the Phosphoinositide 3-kinases (PI3Ks)/AKT serine-threonine protein kinase (AKT) axis, which inactivates Glycogen synthase kinase (GSK) 3β through phosphorylation. The inhibited β-catenin destruction complex, which consists of APC regulator of WNT signaling pathways (APC) and Axis Inhibition Protein (AXIN), decreases β-catenin degradation. Accumulated β-Catenin enters the nucleus to bind to transcription factor 3/lymphoid enhancing binding factor 1 (TCF3/LEF1), enhancing VEGF expression (45). ERα and ERβ also directly bind to the VEGF promoter region and increase VEGF expression upon E2 activation (–48).