VEGF, its receptors and the Tie receptors in recurrent miscarriage

Abstract

The aetiology of recurrent miscarriage (at least three consecutive miscarriages) usually remains unsolved. The vascular endothelial growth factor (VEGF) family of proteins, together with their receptors and the Tie (tyrosine kinase with immunoglobulin and epidermal growth factor homology domains) receptors, are crucial for embryonic development. Therefore, we used immunohistochemistry to analyse the expression of VEGF, the VEGF receptors (VEGFR)-1, -2, and -3, and the Tie-1 and Tie-2 receptors in placental and decidual tissue of women with a history of recurrent miscarriage and missed abortion (MA; n = 12) or blighted ovum (BO; n = 6), and from normal early terminated pregnancies (n = 12). Compared with controls, the MA and BO groups showed: (i) diminished placental trophoblastic VEGF immunoreactivity; (ii) weaker VEGFR-1 and -2 immunoreactivity in decidual vascular endothelium; (iii) reduced placental trophoblastic Tie-1 receptor immunoreactivity; and (iv) reduced decidual vascular endothelial Tie-1 and -2 receptor immunoreactivity. The absence of VEGFR-3 immunoreactivity in decidual vascular endothelium was also noted in all study groups. Interestingly, placental villi from the BO group presented blood vessel-like structures negative for von Willebrand factor, but positive for VEGF, VEGFR-1, -2, -3, Tie-1 and Tie-2 receptor. We conclude that the expression of these antigens may be altered in recurrent miscarriages.

Association of angiogenic cytokines (VEGF-A and VEGF-C) and clinical characteristic in women with unexplained recurrent miscarriage

“…The human placenta is rich in angiogenetic growth factors including vascular endothelial growth factor (VEGF), which plays an important role in regulation of forming placental vessels. The role of VEGF family in embryonic development, trophoblast vascularization were reported (23,24).…”

Low VEGF expression in conceptus material and maternal serum AFP and levels as indicators of defective angiogenesis in first-trimester miscarriages

“…Demir et al (29) sugessted that expression of VEGF and its receptors VEFR-1 and VEGFR-2, and angiopoietin receptors Tie-1 and Tie-2 in parallel to vascular maturation in human placental villi during very early stages of placental development. Vuorela et al (31) described diminished placental trophoblastic VEGF immunoreactivity, reduced placental trophoblastic Tie-1 and Tie-2 expression and weaker VEGFR-1, VEGFR-2,Tie-1 and Tie-2 expression in decidual endometrium of spontaneous abortions and these results are similar of our results in which we found that the cytotrophoblasts and syncytiotrophoblasts of the placental villi and endometrial gland cells stained significantly more weakly for VEGF in the patient groups (IA and IU-D) in comparison to the controls. And also they found weak immunostaining for VEGF in vascular endothelium of the placental villi of the healthy controls similar with our study.…”

“…In the same study, the authors showed that, for both VEGF-A and its receptor VEGFR-2 (KDR/flk-1), this stage corresponded to the transition from secondary villi to tertiary villi, which also occurs at 21-32 days post conception (33). The soluble form of VEGF (VEGRF-1) and placental growth factor (PIGF) are expressed during later stages (branching angiogenesis phase), i.e., between 32 days and 25 weeks of gestation (28)(29)(30)(31)(32)(33). Therefore, the levels of serum (soluble) VEGF would not be suitable to predict early pregnancy loss.…”

Angiogenic factors in relation to embryo implantation

“…69 Studies show that a different pattern of expression of angiogenic growth factor is involved in recurrent miscarriage. 70 As with most human studies, whether the unregulated genetic expression of angiogenic growth factor were responsible for a nature of miscarriages is difficult to determine with certainty. There are two mechanisms involved in the formation of blood vessels: vasculogenesis and angiogenesis.…”