Mechanistic and therapeutic implications of angiogenesis in endometriosis

Abstract

Like tumor metastases, endometriotic implants require neovascularization to proliferate and invade into ectopic sites within the host. Endometrial tissue, with its robust stem cell populations and remarkable regenerative capabilities, is a rich source of proangiogenic factors. Among the most potent and extensively studied of these proteins, vascular endothelial growth factor has emerged as a critical vasculogenic regulator in endometriosis. Accordingly, angiogenesis of the nascent endometriotic lesion has become an attractive target for novel medical therapeutics and strategies to inhibit vascular endothelial growth factor action. Vascular endothelial growth factor gene regulation in endometrial and endometriosis cells by nuclear receptors, other transcription factors, and also by infiltrating immune cells is emphasized. New data showing that oxidative and endoplasmic reticulum stress increase vascular endothelial growth factor expression are provided. Finally, we review the clinical implications of angiogenesis in this condition and propose potential antiangiogenic therapies that may become useful in the control or eradication of endometriotic lesions.

Figure 1

Laparoscopic photograph of endometriotic implants on the peritoneum overlying the uterosacral ligament.

Figure 2

The cis-acting sequences in the human VEGF gene promoter. The genomic region extending from −2274 to +745 bp, relative to the transcriptional start site was cloned by Mueller et al and several key transcriptional elements of the promoter are represented. The positions of the cis-regulatory elements are relative but are not spaced precisely. AP-1 = activator protein 1; C/EBP = CCAAT/enhancer binding protein); DR1 = direct repeat 1 (peroxisome proliferator response element and retinoic acid X receptor response element); Egr-1 = early growth response-1; ERE = estrogen response element; PRE/2 = progesterone response element half-site; Smad = this TGF-beta signaling protein derives its name from a contraction of the C. elegans “Sma” and the drosophila “mothers against decapentaplegic” proteins; Sp1 = stimulatory protein 1; TGF-β = transforming growth factor; VEGF = vascular endothelial growth factor.

Figure 3

Endoplasmic reticulum stress results in VEGF upregulation. Endometrial stromal cells were incubated without (control) or with 2.5 μg/mL tunicamycin (Tun) for 16 hours to mimic conditions of ER stress. Vascular endothelial growth factor secreted into the culture supernatant was measured using a standardized ELISA (left ordinate) and VEGF mRNA was quantified in cell lysates by quantitative real-time reverse transcription PCR (qRT-PCR) standardized relative to GAPDH mRNA and normalized to control cultures (right ordinate). A large increase in GRP78 mRNA expression was noted as a positive control for ER stress (described in the text). ER = endoplasmic reticulum; ELISA = enzyme-linked immunosorbent assay; GAPDH = glyceraldehydes-3 phosphate dehydrogenase; mRNA = messenger RNA; PCR = polymerase chain reaction; VEGF = vascular endothelial growth factor.