Regulation of Vascular Endothelial Growth Factor Expression by Estrogens and Progestins

Abstract

Estrogens increase the expression of vascular endothelial growth factor (VEGF) mRNA in the rodent uterus. This regulatory effect is rapid, beginning within 1 hr after hormone treatment, dose dependent, and blocked by the pure antiestrogen ICI 182,780. The induction of the transcript is blocked by inhibitors of RNA but not of protein synthesis, and we have recently identified estrogen response elements in the VEGF gene. Collectively, these findings indicate that estrogens regulate uterine VEGF expression at the transcriptional level via the classical nuclear estrogen receptor pathway. Estrogen induction of VEGF occurs in the stromal layer of the rodent uterus, and estradiol induces expression of VEGF transcript levels in cultured human uterine stromal cells. Progestins also induce VEGF expression in the rodent uterus, although the effect is less marked and slower in onset than estrogenic effects. The effect of progestins is blocked by the antiprogestin mifepristone (RU-486), suggesting that it is also mediated by a classical nuclear receptor pathway. In addition, progestins regulate expression of VEGF mRNA and protein in cultured human T47-D breast cancer cells. The development of uterine leiomyomas is associated with exposure to ovarian sex steroids, abnormal uterine bleeding is commonly seen in patients with leiomyomas, and fibroids require an increased vascular supply for their growth. These observations suggest that VEGF and other angiogenic factors may represent potential targets for the treatment and prevention of uterine fibroids.

Estrogen regulation of placental angiogenesis and fetal ovarian development during primate pregnancy

“…Thus, in the rat uterus estradiol rapidly increased vascular permeability, edema, and endothelial cell mitosis (Astwood, 1938; Friederici, 1967). Estradiol also increased VEGF mRNA levels in vivo in the uterus of nonpregnant rats (Cullinan-Bove and Koos, 1993; Hyder et al , 2000), sheep (Reynolds et al , 1998a) rhesus monkeys (Nayak et al , 2002) and baboons (Niklaus et al , 2002, 2003; Albrecht et al , 2003; Aberdeen et al , 2008) and in vitro in human endometrial cells (Charnock-Jones et al , 1993; Shifren et al , 1996). This stimulatory action of estrogen required the estrogen receptors, because chronic estrogen treatment induced angiogenesis in the uterus of normal but not estrogen receptor-null mice (Johns et al , 1996).…”

RSK in tumorigenesis: Connections to steroid signaling

“…There are several putative mechanisms for estrogen-mediated angiogenesis. Estrogen treatment increases expression of vascular endothelial growth factor (VEGF), a master regulator of angiogenesis, in mouse mammary tumors [131, 132]. Estrogens can also mediate Nitric oxide production, which is essential for VEGF-dependent angiogenesis [129].…”

Gene therapy of benign gynecological diseases

“…Thus, gene therapy of leiomyoma can be executed by switching on the apoptosis mechanism through both extrinsic and intrinsic pathways (by delivering apoptosis-inducing ligands, such as TNF, TRAIL, and FasL; or by delivering pro-apoptotic members of the Bcl-2 family, such as Bax or active caspase molecules). In endometriosis, in addition to estrogen dependency, angiogenesis, which is essential for endometriosis growth, is driven by different growth factors such as basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and platelet-derived endothelial growth factor (PDGF)[137–140]. Each of these angiogenic factors represents a potential gene therapy target.…”