Expression of Vascular Endothelial Growth Factor (VEGF), Hypoxia Inducible Factor-1α (HIF-1α), and Microvessel Density in Endometrial Tissue in Women With Adenomyosis

Abstract

Adenomyosis is a disease with a mysterious pathogenesis, defined by an abnormal displacement of the eutopic endometrium deeply and haphazardly inside the myometrium. Angiogenesis has been indicated to play an important role and our aim was to investigate whether vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1alpha (HIF-1alpha) expression and microvessel density (MVD) were different in women with and without adenomyosis. Immunohistochemistry was performed in endometrial tissues in 23 patients who underwent radical hysterectomy for adenomyosis (14) and for ovarian cysts and fibroids (9) at an Academic Hospital. Compared to women without the disease, VEGF expression was increased in endometrium with a normal location in patients with adenomyosis, although not associated to a significant increase of HIF-1alpha and MVD. Moreover, the endometrium with an abnormal location in patients with adenomyosis showed an increased VEGF and HIF-1alpha expression, particularly in the epithelial cells, associated to an increase of MVD, compared with the endometrium in a normal location in the same group of patients. Our present findings suggest that VEGF-mediated angiogenesis might be associated with the development of adenomyosis. In the ectopic foci the abnormal location might contribute to increased HIF-1a expression, stimulation of VEGF production, and increased vessel formation. In endometrium with a normal location, instead, where VEGF increased expression seems not to be correlated with HIF-1alpha increased expression nor with an increased MVD, other mechanisms might be reasonably postulated. Additional studies are required to explore new targeted and more effective treatment modalities.

Adenomyosis and infertility

“…Similar results for MMP2 were obtained by Tokyol et al (2009). Subsequently, Goteri et al (2009) compared in the same women the expression of VEGF and hypoxia-inducible factor-1a (HIF-1a) by heterotopic versus normotopic endometrium in women with adenomyosis and found that both were increased, particularly in epithelial cells. Furthermore, Kang et al (2009) investigated four VEGF polymorphic alleles and found significant differences between adenomyosis patients and a control group in the allele frequencies and genotype distributions.…”

Proangiogenetic molecules, hypoxia-inducible factor-1α and nitric oxide synthase isoforms in ovarian endometriotic cysts

“…Hypoxia-inducible factor-1 (HIF-1) is a master transcription factor that mediates the hypoxic effect and plays a key role in VEGF-induced angiogenesis [20,21]. Recent data indicate a possible role for HIF-1 in the pathogenesis and development of endometriosis and adenomyosis [21][22][23]. NO is a lipid-soluble gaseous free radical produced during the enzymatic conversion of L-arginine to L-citrulline by NO synthase (NOS) enzyme and involved in both inflammation and neoangiogenesis [24,25].…”

The effect of adenomyosis on the outcomes of laparoscopic hysterectomy

“…The structure of vessels supplying a large uterus becomes thicker (22). Goteri et al (4) claimed that there has been a marked increase in the development of microvessels in patients with ADS. The lesions of ADS have been shown to be hypervascularized tissues due to high VEGF content (23).…”

“…The prevalence of ADS in hysterectomy specimens was found to be 28.2% in a study (2). Studies have demonstrated the occurrence of invasive adenomyotic lesions associated with increased levels of matrix metalloproteinases (MMPs) and showed increased levels of vascular endothelial growth factor (VEGF) in patients with ADS (3,4). The progressive enlargement of the uterus due to adenomyotic lesions is considered to cause symptoms such as abnormal uterine bleeding (AUB), dysmenorrhea, and uterine tenderness (5).…”