ES, a bioactive C-terminus proteolytic cleavage fragment of extracellular matrix collagen XVIII, inhibits migration/proliferation of cancer epithelial cells. ES has powerful anti-angiogenic activities via down-regulation of vascular endothelial growth factor (VEGF), which is modulated by HIF-1α signaling. We hypothesized that in focal areas of excessive trophoblast invasion, ES interferes with angiogenesis and HIF-1α induction of VEGF.
We explored serum levels of ES and HIF-1α in 22 patients with histological-confirmed invasive placentation (GA: 29±5w, accreta: n=5; increta: n=11; percreta: n=6) by ELISA and Western blot. Samples (total n=30) were retrieved prospectively and in a serial fashion prior to blood transfusion or steroids. We controlled for pregnancy and possible GA variation using blood samples (n=43) of 10 healthy nonpregnant and 10 healthy pregnant (GA: 26±9w) subjects. Full-thickness myometrial-villous hysterectomy sections were immunostained and scored for ES, HIF-1α, VEGF, and cytokeratin-7 (CK7, epithelial cell marker). Myometrium opposite from the accreta insertion site and normal placental bed biopsies (n=4) served as tissue controls (CRL).
In CRL subjects, systemic ES levels were unaffected by pregnancy status or GA (P=.752), while serum HIF-1α was undetectable. Women with advanced trophoblast invasion (increta & percreta) had lower serum levels of ES compared with less invasion (accreta) (P=.009). The site of excessive trophoblast invasion (+CK7) lacked immunostaining for ES and HIF-1α relative to the deeper myometrium and the opposite myometrial site (P<.001). In an opposing pattern, VEGF was highly expressed at the site of excessive myometrial invasion and aberrant vascularization (P<.001).
The local imbalance among expression of ES and VEGF likely contributes to the invasive phenotype of the accreta trophoblasts. This effect seems to occur independent of HIF-1α.
© 2013 Mosby, Inc. Published by Elsevier Inc. All rights reserved.