The protective effects of estrogen on the cardiovascular system

Estrogens and estrogen-like substances are widely distributed in animals and plants, and it is now clear that estrogens have both nuclear and nonnuclear actions. This review article summarizes the production, metabolism, and actions of estrogens, with particular attention to the nuclear actions of estrogens and the mechanisms that underlie the different estrogen-agonist and estrogen-antagonist actions of selective estrogen-receptor–modulating drugs.

Production and actions of estrogens.

Estrogen has direct and indirect effects on the cardiovascular system that are mediated by the estrogen receptors ER-a and ER-β. The direct effects of estrogen occur through rapid nongenomic and longer-term genomic pathways. The rapid effects of estrogen are mediated by ERs and result in the activation of endothelial nitric oxide synthase, leading to arterial vasodilation. Longer-term effects involve changes in gene and protein expression, modulating the response to injury and atherosclerosis. Estrogen also indirectly influences serum lipoprotein and triglyceride profiles, and the expression of coagulant and fibrinolytic proteins. Advanced atherosclerosis and certain progestins, however, may attenuate some of the protective effects of estrogen.

Protective effects of estrogen on the cardiovascular system. Discussion

Estrogens mediate profound effects throughout the body and regulate physiological and pathological processes in both women and men. The low prevalence of many diseases in premenopausal women is attributed to the presence of 17β-estradiol, the predominant and most potent endogenous estrogen. In addition to endogenous estrogens, several man-made and plant-derived molecules, such as bisphenol A and genistein, also exhibit estrogenic activity. Traditionally, the actions of 17β-estradiol are ascribed to two nuclear estrogen receptors (ERs), ERα and ERβ, which function as ligand-activated transcription factors. However, 17β-estradiol also mediates rapid signaling events via pathways that involve transmembrane ERs, such as G-protein-coupled ER 1 (GPER; formerly known as GPR30). In the past 10 years, GPER has been implicated in both rapid signaling and transcriptional regulation. With the discovery of GPER-selective ligands that can selectively modulate GPER function in vitro and in preclinical studies and with the use of Gper knockout mice, many more potential roles for GPER are being elucidated. This Review highlights the physiological roles of GPER in the reproductive, nervous, endocrine, immune and cardiovascular systems, as well as its pathological roles in a diverse array of disorders including cancer, for which GPER is emerging as a novel therapeutic target and prognostic indicator.

/pdf/the-g-protein-coupled-estrogen-receptor-gper-in-health-and-3zacz398rx.pdf

The G-protein-coupled estrogen receptor GPER in health and disease

A protocol is presented here for a rapid, quantitative and reliable in vitro angiogenesis assay that can be adapted for high throughput use. Endothelial cells are plated on a gelled basement matrix, their natural substrate, and form capillary-like structures with a lumen. The assay can be used to identify inhibitors or stimulators of angiogenesis, as well as genes and signaling pathways involved in angiogenesis. It has also been used to identify endothelial progenitor cells. This assay involves endothelial cell adhesion, migration, protease activity and tubule formation. This tube formation assay is preferred, as other in vitro assays for angiogenesis, such as cell adhesion, migration and invasion, measure limited steps in the angiogenesis process. The tube formation assay on basement membrane can be completed in a day because transformed endothelial cells form tubes within 3 h, whereas non-transformed endothelial cells form tubes within 6 h.

In vitro angiogenesis: endothelial cell tube formation on gelled basement membrane extract

Background Angiogenesis is a critical event in wound healing, tumor growth, and the inflammatory vasculitides. Since women have a higher incidence of many vasculitic diseases, we examined the effects of female sex steroids, particularly estradiol, on human umbilical vein endothelial cell (HUVEC) behavior in vitro and on angiogenesis in vivo. Methods and Results HUVECs were grown in estrogen-free medium before each assay. Exogenous 17β-estradiol (1 to 5 nmol/L) increased cell attachment to laminin, types I and IV collagen, and fibronectin, as well as to tissue culture plastic. After a confluent monolayer of cells was “wounded” by scraping, estradiol-treated (10−8 mol/L) cells migrated into the wound three times faster than untreated cells. Cell proliferation on plastic and on laminin increased threefold to fivefold, respectively, in the presence of estradiol. Estradiol also enhanced the ability of HUVECs to organize into tubular networks when plated on a reconstituted basement membrane, Matrigel. Estradiol...

Estrogen Promotes Angiogenic Activity in Human Umbilical Vein Endothelial Cells In Vitro and in a Murine Model

The molecular mechanisms involved in the dynamic interaction of human breast carcinoma cells with the endothelial cell lining of lymphatic vessels and post-capillary blood venules are largely unknown. In the present study, laminar flow assays were used to investigate the ability of various normal breast cells and of breast- and colon-tumor cells to adhere to human umbilical cord endothelial cell monolayers. MCF-10A breast, MCF-7 and T-47D breast-carcinoma and clone A, RKO, and HT-29 colon-carcinoma cells accumulated and rolled, in the presence of flow, on tumor necrosis factor (TNF)-stimulated but not on unstimulated endothelial cell monolayers. Non-tumor and tumor cells continued to form transient adhesions with TNF-stimulated endothelial cells even when the flow rate was increased to levels found in arteries. Incubation of TNF-stimulated endothelial cells with an E-selectin-specific monoclonal antibody (MAb) partially or completely inhibited dynamic interactions and diminished adhesion strength, whereas integrin beta 1- and integrin alpha 6-specific MAbs had no effect. A set of highly invasive breast-carcinoma cells (MDA-231, BT-549, HS-578t) neither adhered to nor rolled on resting or TNF-stimulated endothelial cell monolayers. However, after 5 min of static incubation, a fraction of these cells attached strongly to resting and TNF-stimulated endothelial cells and this static adhesion could not be blocked by an E-selectin-specific monoclonal antibody. Our results suggest that E-selectin is a major homing receptor in the metastasis of some breast and colon cancers.

E-selectin-mediated dynamic interactions of breast- and colon-cancer cells with endothelial-cell monolayers

[PSI+] yeast, containing the misfolded amyloid conformation of Sup35 prion, is cured by inactivation of Hsp104. There has been controversy as to whether inactivation of Hsp104 by guanidine treatment or by overexpression of the dominant negative Hsp104 mutant, Hsp104-2KT, cures [PSI+] by the same mechanism– inhibition of the severing of the prion seeds. Using live cell imaging of Sup35-GFP, overexpression of Hsp104-2KT caused the foci to increase in size, then decrease in number, and finally disappear when the cells were cured, similar to that observed in cells cured by depletion of Hsp104. In contrast, guanidine initially caused an increase in foci size but then the foci disappeared before the cells were cured. By starving the yeast to make the foci visible in cells grown with guanidine, the number of cells with foci was found to correlate exactly with the number of [PSI+] cells, regardless of the curing method. Therefore, the fluorescent foci are the prion seeds required for maintenance of [PSI+] and inactivation of Hsp104 cures [PSI+] by preventing severing of the prion seeds. During curing with guanidine, the reduction in seed size is an Hsp104-dependent effect that cannot be explained by limited severing of the seeds. Instead, in the presence of guanidine, Hsp104 retains an activity that trims or reduces the size of the prion seeds by releasing Sup35 molecules that are unable to form new prion seeds. This Hsp104 activity may also occur in propagating yeast.

/pdf/differences-in-the-curing-of-psi-prion-by-various-methods-of-2ywmsr9zy9.pdf

Differences in the curing of [PSI+] prion by various methods of Hsp104 inactivation.

During development, blood vessels are rapidly formed from angioblasts in the mesoderm. This is followed by extensive branching of the vessels to supply the needs of the growing tissue. In the adult, however, vessels form a complex and stable network providing a transit-way for blood cells, oxygen, growth factors, hormones, etc., to all tissues. Usually changes in the vasculature occur only in response to injury stimulation, or cyclic changes in the female reproductive system. When induced to become angiogenic, the endothelial and smooth muscle cells enter a migratory and proliferative phase resulting in a reorganization of the vessel wall and the formation of new blood vessels. This involves a cascade of sequential events leading to endothelial cell invasion into the underlying stroma, and the formation of new blood vessels leading away from the parent vessel towards the stimulus 1,2 .

Angiogenesis Models Identify Factors Which Regulate Endothelial Cell Differentiation

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Estrogen Promotes Angiogenic Activity in Human Umbilical Vein Endothelial Cells In Vitro and in a Murine Model

E-selectin-mediated dynamic interactions of breast- and colon-cancer cells with endothelial-cell monolayers

Differences in the curing of [PSI+] prion by various methods of Hsp104 inactivation.

Angiogenesis Models Identify Factors Which Regulate Endothelial Cell Differentiation