Estradiol enhances endothelial cell interactions with extracellular matrix proteins via an increase in integrin expression and function (original) (raw)
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Effect of estrogen on endothelial function and angiogenesis
Vascular Pharmacology, 2002
Animal studies evaluating gender difference, the effects of gonadectomy and estrogen replacement and clinical studies in postmenopausal women with and without estrogen replacement therapy (ERT) proved that estrogen exerts significant benefits on the cardiovascular system. Since effects on the plasma lipoprotein profile is responsible for only $25-40% of the cardiovascular protection exerted by estrogens, it is postulated that direct effects of estrogen on the vascular wall must play an important role. Indeed, experimental and clinical evidence accumulated over the past decade, and reviewed briefly here, indicate that at least a part of cardiovascular benefits of 17bestradiol can be attributed to the direct effect of the ovarian sex steroid hormone on vascular endothelial cells. Maintenance and upregulation of endothelial nitric oxide production and suppression of EDCF generation by 17b-estradiol may play an important role in preventing or reversing endothelial dysfunction, associated with atherosclerosis, hypertension and other cardiovascular diseases. Stimulation of angiogenesis (especially collateral vessel formation in ischemic tissues) by the ovarian steroid hormone could be beneficial in coronary artery disease, peripheral vascular disease, cerebral ischemia (stroke) and congestive heart failure. Despite these indisputable beneficial effects, several key questions remain to be answered in the future, including the better understanding of the apparently opposite effects of estrogen on prevention of cardiovascular disease vs. treatment of existing disease.
Hypertension, 2007
Venous complications have been implicated in the adverse effects of hormone replacement therapy. This study investigated acute effects of the natural estrogen, 17-estradiol, on function, estrogen receptors/GPR30 expression, and kinase activation in vascular rings and cultured smooth muscle cells from arteries and veins of patients with coronary artery disease. Changes in vascular tone of internal mammary arteries and saphenous veins exposed to the steroid were recorded. 17-Estradiol caused concentration-dependent, endothelium-independent relaxation in arteries (PϽ0.05 versus solvent control) but not in veins (P not significant). 17-Estradiol enhanced contractions to endothelin-1 in veins but not in arteries. The novel membrane estrogen receptor GPR30 was detected in both vessels. Moreover, gene expression of estrogen receptor  was 10-fold higher than that of estrogen receptor ␣ or GPR30 (PϽ0.05). Expression of all 3 of the receptors was reduced after exposure to 17-estradiol in arteries but not in veins (PϽ0.05). Basal phosphorylation levels of extracellular signal-regulated kinase were higher in venous than in arterial smooth muscle cells and were increased by 17-estradiol in arterial cells only. In summary, this is the first study to report that, in human arteries but not in veins, 17-estradiol acutely affects vascular tone, estrogen receptor expression, including GPR30, and extracellular signal-regulated kinase phosphorylation. These data indicate that effects of natural estrogens in humans differ between arterial and venous vascular beds, which may contribute to the vascular risks associated with menopause or hormone therapy.
Atherosclerosis, 2002
Background: Intervention trials in postmenopausal women with coronary artery disease have failed to demonstrate beneficial effects of hormone replacement therapy (HRT) on the course of disease, potentially due to pro-inflammatory effects of conjugated equine estrogens. We characterized the effects of 48 weeks treatment with two estradiol-based HRT regimens on nonspecific (high sensitivity C-reactive protein [hs-CRP], blood sedimentation rate [BSR], fibrinogen) and specific endothelial markers (cell adhesion molecules: ICAM-1, VCAM-1, E-selectin). Method and Results: Postmenopausal women randomly received either 1 mg 17bestradiol daily plus 25 mg gestodene for the last 12 days of each 28 day cycle (0/standard dose progestin; n 0/65), or gestodene added each third cycle only (0/low dose progestin; n 0/65), or no HRT (n 0/73). Both HRT regimens reduced levels of ICAM-1 ((/9%), VCAM-1 ((/9%), E-selectin ((/11%), fibrinogen ((/12%), BSR ((/5%). No effect was observed on hs-CRP levels in any group. In smokers, E-selectin remained unchanged whereas ICAM-1 and VCAM-1 were lowered. Subjects on antihypertensive or lipid lowering medication showed effects comparable to the whole cohort. Effects of low and standard dose progestin were not different. Conclusion: We conclude that a combination therapy with 1 mg 17b-estradiol favourably affects the vascular inflammation processes as indicated by a neutral effect on hs-CRP and reduction of cell adhesion molecules.
Estrogen improves endothelial function
Journal of Vascular Surgery, 1998
Purpose: To determine the effect of estrogen on endothelium-dependent rdaxation in the cutaneous microcirculation of women.
Estradiol Stimulates Vasodilatory and Metabolic Pathways in Cultured Human Endothelial Cells
PLoS ONE, 2009
Vascular effects of estradiol are being investigated because there are controversies among clinical and experimental studies. DNA microarrays were used to investigate global gene expression patterns in cultured human umbilical vein endothelial cells (HUVEC) exposed to 1 nmol/L estradiol for 24 hours. When compared to control, 187 genes were identified as differentially expressed with 1.9-fold change threshold. Supervised principal component analysis and hierarchical cluster analysis revealed the differences between control and estradiol-treated samples. Physiological concentrations of estradiol are sufficient to elicit significant changes in HUVEC gene expression. Notch signaling, actin cytoskeleton signaling, pentose phosphate pathway, axonal guidance signaling and integrin signaling were the top-five canonical pathways significantly regulated by estrogen. A total of 26 regulatory networks were identified as estrogen responsive. Microarray data were confirmed by quantitative RT-PCR in cardiovascular meaning genes; cyclooxigenase (COX)1, dimethylarginine dimethylaminohydrolase (DDAH)2, phospholipase A2 group IV (PLA2G4) B, and 7-dehydrocholesterol reductase were upregulated by estradiol in a dose-dependent and estrogen receptor-dependent way, whereas COX2, DDAH1 and PLA2G4A remained unaltered. Moreover, estradiol-induced COX1 gene expression resulted in increased COX1 protein content and enhanced prostacyclin production. DDAH2 protein content was also increased, which in turn decreased asymmetric dimethylarginine concentration and increased NO release. All stimulated effects of estradiol on gene and protein expression were estrogen receptor-dependent, since were abolished in the presence of the estrogen receptor antagonist ICI 182780. This study identifies new vascular mechanisms of action by which estradiol may contribute to a wide range of biological processes.
The Journal of Clinical Endocrinology & Metabolism, 2002
Estrogen has a cardiovascular protective role in women due in part to its effect on the vasculature. The roles of the two estrogen receptors (ERs), ER␣ and ER, in the vascular actions of estrogen are unclear, as are effects of estrogen on microvascular endothelial cells (MEC) derived from sex steroid-responsive tissues. The present study demonstrates that 17-estradiol, but not progesterone, increases vascular endothelial growth factor (VEGF) receptor (VEGFR) expression on human myometrial MEC measured using biotin-recombinant human (rh) VEGF 165 and flow cytometry. This response occurred in a time-and dose-dependent manner, with significantly increased rhVEGF 165 binding at 3 h and maximal responses between 0.1 and 10 nmol/liter 17-estradiol, which was blocked by the antiestrogen ICI 182,780. Approximately 60% of samples demonstrated this response to 17-estradiol. All samples of myometrial MEC expressed both ER mRNA and protein demonstrated by semiquantitative RT-PCR and Western blotting. However, ER␣ mRNA and protein were expressed in only 13 of 21 MEC samples. There was a significant association between ER␣ expression in myometrial MEC and their ability to respond to 17-estradiol by increasing rhVEGF 165 binding. 17-estradiol increased VEGFR-2 expression in ER␣-expressing MEC isolates, which also demonstrated increased rhVEGF 165 binding, but failed to have these effects on ER␣ negative samples. Similarly, 17-estradiol augmented VEGF-induced MEC proliferation in ER␣-expressing MEC samples, which was blocked by ICI 182,780. These observations suggest that 17-estradiol increases VEGFR-2 expression on human myometrial MEC promoting endothelial cell proliferation, an effect that varies between subjects and appears to be mediated primarily by ER␣. (J Clin Endocrinol Metab 87: 4341-4349, 2002)
Hypertension, 2007
Venous complications have been implicated in the adverse effects of hormone replacement therapy. This study investigated acute effects of the natural estrogen, 17β-estradiol, on function, estrogen receptors/GPR30 expression, and kinase activation in vascular rings and cultured smooth muscle cells from arteries and veins of patients with coronary artery disease. Changes in vascular tone of internal mammary arteries and saphenous veins exposed to the steroid were recorded. 17β-Estradiol caused concentration-dependent, endothelium-independent relaxation in arteries ( P <0.05 versus solvent control) but not in veins ( P not significant). 17β-Estradiol enhanced contractions to endothelin-1 in veins but not in arteries. The novel membrane estrogen receptor GPR30 was detected in both vessels. Moreover, gene expression of estrogen receptor β was 10-fold higher than that of estrogen receptor α or GPR30 ( P <0.05). Expression of all 3 of the receptors was reduced after exposure to 17β-e...
Steroids, 2006
Vascular endothelial cell (EC) integrity is key to arterial health; endothelial dysfunction is linked to atherogenesis. Atherosclerosis shows a male preponderance, possibly related to the protective effect of estrogens in women. This study examined the effect of estrogens on growth, apoptosis and adhesion molecule expression in cultured human EC. The effects of 17β-estradiol (E2) were studied in human umbilical vein endothelial cells (HUVEC) under normal culture conditions, and following exposure to cyclic mechanical strain or tumor necrosis factor α (TNFα). E2 enhanced HUVEC growth in serum-enriched media, in a concentration-dependent manner. This up-regulation of EC growth by E2 was associated with an increase in telomerase activity, assessed by PCR-based TRAP analysis. Cyclic strain enhanced [3H]-thymidine incorporation into DNA, and increased activation of mitogen-activated protein (MAP) kinase ERK1/2 and expression of early growth genes (Egr-1 and Sp-1); E2 attenuated the strain-induced ERK1/2 activation but not the early growth gene expression or DNA synthesis. TNFα (20 ng/mL) induced apoptosis in HUVEC, causing a decrease in DNA synthesis, increase in floating and Annexin-V-stained cell numbers, and morphological changes. TNFα also upregulated ERK1/2 activity and expression of adhesion molecules (ICAM-1, VCAM-1 and E-selectin). E2 significantly attenuated the effects of TNFα on ERK1/2 activity, apoptosis, and E-selectin expression in the cells. Thus, estradiol enhances growth and reduces TNFα-induced apoptosis in EC; enhanced EC growth may be mediated via upregulation of telomerase activity. These effects are possible cellular mechanisms underlying female gender-associated cardiovascular protection.