Estudio del papel de la proteína Kinasa C y del estrés oxidativo en la fisiopatología de la neuropatía diabética experimental

Therapeutic dosages of oral or transdermal estradiol did not modify sCD40L levels in postmenopausal women.

The CD40/CD40L system is considered a crucial modulator of the inflammatory process underlying the progression and complication of atheroma plaques. The soluble fraction of CD40L (sCD40L) is a reliable indicator of the CD40/CD40L system. Our purpose was to investigate whether a therapeutic dose of estradiol, by either the oral or the transdermal route, was associated with changes in circulating levels of sCD40L. Forty-seven women completed a 4-week course of treatment with either oral estradiol valerate (2 mg/day, 20 women) or transdermal estradiol (50 microg/day, 27 women). Serum levels of sCD40L were measured by conventional enzyme-linked immunosorbent assay. Oral, but not transdermal est…

Usefulness of Clinical Data and Biomarkers for the Identification of Frailty After Acute Coronary Syndromes

Abstract Background Frailty predicts mortality after acute coronary syndrome (ACS). The standard frailty scales, such as the Fried score, consist of a variety of questionnaires and physical tests. Our aim was to investigate easily available clinical data and blood markers to predict frailty at discharge, in elderly patients after ACS. Methods A total of 342 patients older than 65 years, survivors after ACS, were included. A high number of clinical variables were collected. In addition, blood markers potentially linked to frailty and related to the processes of inflammation, coagulation, hormonal dysregulation, nutrition, renal dysfunction, and heart dysfunction were determined. Frailty was …

An affordable method to obtain cultured endothelial cells from peripheral blood

The culture of endothelial progenitor cells (EPC) provides an excellent tool to research on EPC biology and vascular regeneration and vasculogenesis. The use of different protocols to obtain EPC cultures makes it difficult to obtain comparable results in different groups. This work offers a systematic comparison of the main variables of most commonly used protocols for EPC isolation, culture and functional evaluation. Peripheral blood samples from healthy individuals were recovered and mononuclear cells were cultured. Different recovery and culture conditions were tested: blood volume, blood anticoagulant, coating matrix and percentage of foetal bovine serum (FBS) in culture media. The succ…

Endothelial and neural factors functionally involved in the modulation of noradrenergic vasoconstriction in healthy pig internal mammary artery

The role of endothelial and neural factors as modulators of neurogenic- and noradrenaline-induced vasoconstriction was examined in healthy pig internal mammary artery (IMA). Tetrodotoxin-, guanethidine-sensitive electrical field stimulation (EFS)-, and noradrenaline-elicited contractions were significantly diminished by prazosin (n=8, P0.001) and less so by rauwolscine, indicating functional α₁- and α₂-adrenoceptor-mediated noradrenergic innervation of the IMA. Endothelium removal reduced neurogenic (n=8, P0.01) but augmented noradrenaline responses (n=8, P0.01), suggesting the release of two endothelium-dependent factors with opposite effects. In the presence of endothelium, neurogenic and…

Extracellular histones trigger oxidative stress-dependent induction of the NF-kB/CAM pathway via TLR4 in endothelial cells.

Abstract Extracellular histones have been reported to aggravate different pathophysiological processes by increasing vascular permeability, coagulopathy, and inflammation. In the present study, we elucidate how extracellular histones (10–100 µg/mL) concentration dependently increase cytosolic reactive oxygen species (ROS) production using human umbilical vein endothelial cells (HUVECs). Furthermore, we identify cyclooxygenase (COX) and NADPH oxidase (NOX) activity as sources of ROS production in extracellular histone-treated HUVEC. This COX/NOX-mediated ROS production is also involved in enhanced NF-kB activity and cell adhesion molecules (VCAM1 and ICAM1) expression in histone-treated HUVE…

Estradiol induces endothelial cell migration and proliferation through estrogen receptor-enhanced RhoA/ROCK pathway

Migration and proliferation of endothelial cells are involved in re-endothelialization and angiogenesis, two important cardiovascular processes that are increased in response to estrogens. RhoA, a small GTPase which controls multiple cellular processes, is involved in the control of cell migration and proliferation. Our aim was to study the role of RhoA on estradiol-induced migration and proliferation and its dependence on estrogen receptors activity. Human umbilical vein endothelial cells were stimulated with estradiol, in the presence or absence of ICI 182780 (estrogen receptors antagonist) and Y-27632 (Rho kinase inhibitor). Estradiol increased Rho GEF-1 gene expression and RhoA (gene an…

Estradiol Stimulates Vasodilatory and Metabolic Pathways in Cultured Human Endothelial Cells

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 cyt…

Estradiol counteracts oxidized LDL-induced asymmetric dimethylarginine production by cultured human endothelial cells.

Objective: Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide (NO) synthase, is a novel cardiovascular risk factor produced by endothelial cells. ADMA levels are mainly regulated by the activity of dimethylarginine dimethylaminohydrolases (DDAH). Endothelial release of ADMA is increased in the presence of oxidized LDL cholesterol (oxLDL), whereas estrogens stimulate NO production by endothelial cells by increasing both expression and activity of NO synthase and by reducing ADMA levels. Thus, the aim of the present study was to evaluate the estradiol effects on the DDAH/ADMA/NO pathway in cultured human umbilical vein endothelial cells (HUVEC) exposed to LDL. Methods…

Delayed Fatherhood in Mice Decreases Reproductive Fitness and Longevity of Offspring1

Abstract This study aims to analyze, in mice, the long-term effects of delayed fatherhood on reproductive fitness and longevity of offspring. Hybrid parental-generation (F0) males, at the age of 12, 70, 100, and 120 wk, were individually housed with a randomly selected 12-wk-old hybrid female. The reproductive fitness of first-generation (F1) females was tested from the age of 25 wk until the end of their reproductive life. In F1 males, the testing period ranged from the age of 52 wk until death. Breeding F1 females from the 120-wk group displayed interbirth intervals longer than females from the 12-, 70-, and 100-wk groups. Furthermore, F2 pups begotten by F1 studs exhibited weaning weight…

Changes in sex ratio from fertilization to birth in assisted-reproductive-treatment cycles

Background: In Western gender-neutral countries, the sex ratio at birth is estimated to be approximately 1.06. This ratio is lower than the estimated sex ratio at fertilization which ranges from 1.07 to 1.70 depending on the figures of sex ratio at birth and differential embryo/fetal mortality rates taken into account to perform these estimations. Likewise, little is known about the sex ratio at implantation in natural and assisted-reproduction-treatment (ART) cycles. In this bioessay, we aim to estimate the sex ratio at fertilization and implantation using data from embryos generated by standard in-vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) in preimplantation gene…

Complete blockade of the vasorelaxant effects of angiotensin-(1-7) and bradykinin in murine microvessels by antagonists of the receptor Mas

Key points • Two distinct angiotensin-(1–7) [Ang-(1–7)] receptor blockers, A779 and d-Pro-Ang-(1–7), can completely prevent Ang-(1–7)-induced vasorelaxation. • Genetic deficiency of Mas completely prevents vascular responses to Ang-(1–7). • Genetic deficiency of Mas completely prevents vascular responses to other NO-dependent vasorelaxants (bradykinin). • Mas plays a key role in NO-mediated vasodilatation by modulating vasorelaxant-mediated phosphorylation of endothelial nitric oxide synthase in endothelial cells. Abstract  The heptapeptide angiotensin-(1–7) is a biologically active metabolite of angiotensin II, the predominant peptide of the renin–angiotensin system. Recently, we have show…

Effect of delayed breeding on the reproductive performance of female mice

The aim of the present study was to determine, in the mouse, whether maintaining females as virgins until an advanced reproductive age was associated with decreased reproductive performance and reproductive lifespan compared with females of the same age that were first mated with males at an earlier reproductive age. Randomly selected virgin hybrid (C57BL/6JIco female × CBA/JIco male) female mice were housed individually with a randomly selected 12- to 14-week-old hybrid male either at the age of 28 weeks (normal breeding group; n = 20) or 51 weeks (delayed breeding group; n = 23) for the rest of their reproductive life. Females were checked once daily to determine the day of parturition an…

Raloxifene promotes prostacyclin release in human endothelial cells through a mechanism that involves cyclooxygenase-1 and -2

Objective To examine the effects of raloxifene on prostacyclin production by human umbilical vein endothelial cells (HUVEC) and to shed light on the molecular details of that action. Design Cell culture for 4, 8, 16, 24, and 48 hours. Setting University research laboratory. Patient(s) Source of HUVEC. Intervention(s) Measurement of prostacyclin production and of protein levels and mRNA expression of cyclooxygenase (COX)-1 and -2. Main Outcome Measure(s) Prostacyclin production was measured by enzyme immunoassay, the mRNA expression of COX-1 was measured by quantitative real time-polymerase chain reaction, and the protein levels of COX-1 and -2 were measured by immunoblotting. Result(s) Ralo…

Long-Term Effects of Postovulatory Aging of Mouse Oocytes on Offspring: A Two-Generational Study1

Aims of this study were to analyze the long-term effects of postovulatory aging of mouse oocytes on 1) reproductive traits of parental (F(0)) and first (F(1))-generation females (pregnancy rate, gestation length, litter size, perinatal death, and sex ratio of offspring) and 2) developmental and behavioral variables of F(1) and second-generation (F(2)) offspring (birth weight and weight gain during preweaning development, postnatal day of attainment of immediate righting, spontaneous motor activity, and passive and active conditioned learning ability). Hybrid (C57BL/6JIco x CBA/JIco) females were artificially inseminated at 13 h (control group) or 22 h (oocyte-aged group) after GnRH injectio…

Metabolismo lipídico y aterogénesis femenina: acción de hormonas, SERM y fitoestrógenos

Resumen Objetivo Revisar los efectos de la terapia hormonal sustitutiva, en sus distintas formas, en el metabolismo lipidico Fuentes Bibliografia medica hasta septiembre del ano 2000 a traves de MEDLINE Conclusiones Los estrogenos, combinados o no con progestagenos, inducen un perfil lipoproteico favorable. Buena parte de esa accion se ejerce a traves de modificacion en la cinetica de particulas. Las acciones sobre oxidacion de las lipoproteinas de baja densidad (LDL), o el tamano de sus particulas, son motivo de polemica. Nuevos preparados, con capacidad de activar receptores estrogenicos, tambien demuestran ejercer acciones selectivas sobre el metabolismo lipidico

Delayed Motherhood Decreases Life Expectancy of Mouse Offspring1

Abstract This study analyzes the long-term effects of delayed motherhood on reproductive fitness and life expectancy of offspring in the mouse. Hybrid (C57BL/6JIco × CBA/JIco) first-generation (F1) females, either at the age of 10 or 51 wk, were individually housed with a randomly selected 12- to 14-wk-old hybrid male following a breeding pen system until females reached the end of their reproductive life. Reproductive fitness of second-generation (F2) females was tested from the age of 25 wk until the end of their reproductive life. In F2 males, the testing period ranged from the age of 52 wk until their natural death. Delayed motherhood of hybrid F1 female mice was associated with a decre…

Estradiol, acting through estrogen receptor alpha, restores dimethylarginine dimethylaminohydrolase activity and nitric oxide production in oxLDL-treated human arterial endothelial cells

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide (NO) synthase. ADMA accumulation, mainly due to a decreased dimethylarginine dimethylaminohydrolase (DDAH) activity, has been related to the development of cardiovascular diseases. We investigate whether estradiol prevents the changes induced by oxidized low density lipoprotein (oxLDL) on the DDAH/ADMA/NO pathway in human umbilical artery endothelial cells (HUAEC). HUAEC were exposed to estradiol, native LDL (nLDL), oxLDL and their combinations for 24 h. In some experiments, cells were also exposed to the unspecific estrogen receptor (ER) antagonist ICI 182780, the specific ERα antagonist MPP or specific agonists …

Endothelial transcriptomic changes induced by oxidized low density lipoprotein disclose an up-regulation of Jak-Stat pathway.

Oxidized low density lipoproteins (oxLDLs) act as an etiological factor in the development of atherosclerosis by modifying the biological properties of endothelial cells through mechanisms of vascular inflammation. To deepen the oxLDL changes at cellular level, a transcriptomic analysis of human umbilical artery endothelial cells (HUAECs) treated with oxLDL was performed to identify the modified signaling pathways. Total RNA was isolated from HUAECs treated with oxLDL (100 μg/ml). Gene expression analysis was carried out using Affymetrix oligonucleotide microarrays. Biological pathway analysis was performed using Ingenuity Pathway Analysis software. Microarray assay demonstrated that oxLDL …

Diminished neurogenic femoral artery vasoconstrictor response in a Zucker obese rat model: differential regulation of NOS and COX derivatives.

Objective: Peripheral arterial disease is one of the macrovascular complications of type 2 diabetes mellitus. This study addresses femoral artery regulation in a prediabetic model of obese Zucker rats (OZR) by examining cross-talk between endothelial and neural factors. Methods and Results: Arterial preparations from lean (LZR) and OZR were subjected to electrical field stimulation (EFS) on basal tone. Nitric oxide synthase (NOS) and cyclooxygenase (COX) isoform expression patterns were determined by immunohistochemical labelling and Western blotting. Results indicate significantly reduced noradrenergic contractions in preparations from OZR compared with those of LZR. Functional inhibition …

Long-Term Effects of Delayed Fatherhood in Mice on Postnatal Development and Behavioral Traits of Offspring1

This study aims to analyze, in mice, the long-term effects of delayed fatherhood on postnatal development, spontaneous motor activity, and learning capacity of offspring. Hybrid parental-generation (F 0 ) males, at the age of 12, 70, 100, and 120 wk, were individually housed with a randomly selected 12wk-old hybrid female. The resulting first-generation (F 1 ) offspring were tested for several developmental and behavioral variables. Cumulative percentage of F 1 pups that attained immediate righting in the 120-wk group was lower than that found in the 12-, 70-, and 100-wk groups. Furthermore, the postnatal day of attaining immediate righting was higher in pups from the 120-wk group when comp…

Aging enhances contraction to thromboxane A2 in aorta from female senescence mice

The time-course for aging-associated effects on vascular reactivity to U46619, a stable analogue of thromboxane A2 (TXA2), was studied in aorta from female senescence-accelerated mice-prone (SAMP8), a murine model of accelerated senescence. SAMP8 and senescence-accelerated mice-resistant (SAMR1) were divided into three groups: 3-, 6- and 10-month-old. Contractile curves to U46619 (10−9 to 10−6 M) were performed in aortic rings in the absence or in the presence of nitric oxide synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 10−4 M) and/or cyclooxygenase (COX) inhibitor indomethacin (10−5 M). Protein and gene expression for COX-1 and COX-2 were determined by immunofluoresce…

Selective estrogen receptor modulators and risk for coronary heart disease.

Coronary heart disease (CHD) is the leading cause of death in women in most countries. Atherosclerosis is the main biological process determining CHD. Clinical data support the notion that CHD is sensitive to estrogens, but debate exists concerning the effects of the hormone on atherosclerosis and its complications. Selective estrogen receptor modulators (SERMs) are compounds capable of binding the estrogen receptor to induce a functional profile distinct from estrogens. The possibility that SERMs may shift the estrogenic balance on cardiovascular risk towards a more beneficial profile has generated interest in recent years. There is considerable information on the effects of SERMs on disti…

Predictive variables of in vitro fertilization and pre-implantation embryo development in the mouse

The present study aims to analyze the cause-effect relationships among several in-vitro fertilization and pre-implantation embryo development variables in the mouse. Superovulation of hybrid (C57Bl/6JIco female X CBA/JIco male) female mice of 4-6 weeks of age was induced by a priming injection of pregnant mare's serum gonadotropin at the estrus stage of the estrous cycle followed after a 48-hr interval by human chrorionic gonadotropin. Ovulated cumulus-enclosed oocytes were inseminated with sperm from hybrid males of 12-16 weeks of age. The multiple linear regression analyses performed indicated that (a) total number of ovulated oocytes is a good predictor of both fertilization frequency an…

Plasma concentration of asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, is elevated in hyperthyroid patients.

Cardiovascular manifestations are frequent findings in patients with thyroid hormone disorders. Nitric oxide (NO) plays a key role in vascular, endothelial-mediated relaxation. NO is synthesized from L-arginine by NO synthase, an enzyme inhibited by endogenous compounds, mainly asymmetric dimethylarginine [asymmetric N(G),N(G)-dimethyl-L-arginine (ADMA)]. The aim of our work was to investigate whether plasma L-arginine and dimethylarginine concentrations and NO production are altered in hypo- and hyperthyroid patients, compared with control subjects. L-arginine, ADMA and symmetric dimethylarginine were analyzed by HPLC. NO was measured as plasma nitrite plus nitrate (NO(x)) concentration by…

MicroRNA as crucial regulators of gene expression in estradiol-treated human endothelial cells.

Background/Aims: Estrogen signalling plays an important role in vascular biology as it modulates vasoactive and metabolic pathways in endothelial cells. Growing evidence has also established microRNA (miRNA) as key regulators of endothelial function. Nonetheless, the role of estrogen regulation on miRNA profile in endothelial cells is poorly understood. In this study, we aimed to determine how estrogen modulates miRNA profile in human endothelial cells and to explore the role of the different estrogen receptors (ERα, ERβ and GPER) in the regulation of miRNA expression by estrogen. Methods: We used miRNA microarrays to determine global miRNA expression in human umbilical vein endothelial cel…

Prevention of the acute neurotoxic effects of phenytoin on rat peripheral nerve by H7, an inhibitor of protein kinase C.

Abstract The neurotoxic effects of a single dose of phenytoin (150 mg/kg body weight) alone or 30 min after H7 (a protein kinase C inhibitor) injection (20 mg/kg body weight) were investigated in terms of peripheral neuromuscular function and Na + ,K + -ATPase activity of the sciatic nerve. This intraperitoneal injection of phenytoin induced complete blockade of muscle action potentials in the dorsal segmental muscles of the rat tail evoked by electric stimulation of the caudal nerve and a 40% decrease in the Na + ,K + -ATPase activity of the rat sciatic nerve when compared with control values, measured as the difference between total and ouabain-insensitive ATPase activity. Prior administr…

Some glutathione-related enzymic activities in skeletal muscle and myocardium of the rat : adaptations to endurance training

Aging Negatively Affects Estrogens-Mediated Effects on Nitric Oxide Bioavailability by Shifting ERα/ERβ Balance in Female Mice

AIMS: Aging is among the major causes for the lack of cardiovascular protection by estrogen (E2) during postmenopause. Our study aims to determine the mechanisms whereby aging changes E2 effects on nitric oxide (NO) production in a mouse model of accelerated senescence (SAM). METHODS AND RESULTS: Although we found no differences on NO production in females SAM prone (SAMP, aged) compared to SAM resistant (SAMR, young), by either DAF-2 fluorescence or plasmatic nitrite/nitrate (NO2/NO3), in both cases, E2 treatment increased NO production in SAMR but had no effect in SAMP. Those results are in agreement with changes of eNOS protein and gene expression. E2 up-regulated eNOS expression in SAMR…

Unpredicted ovulations and conceptions during early pregnancy: an explanatory mechanism of human superfetation

In this bioessay, a literature review on human superfetation was performed in order to find epidemiological variables associated with this phenomenon. Thereafter, an explanatory mechanism of superfetation compatible with the endocrinological, histological and physiological changes undergone by women during early pregnancy is proposed. Superfetation can be defined as the ovulation, fertilisation and implantation of a second or additional embryo(s) during pregnancy. The literature review evidences a small discordance in gestational age between dizygotic twins in humans (range: 2–4 weeks; mean ± s.e.m.: 3.3 ± 0.3 weeks). This difference is compatible with a luteal out-of-phase (LOOP; i.e. atyp…

Pure anti-oestrogens

Pure anti-oestrogens are a group of at least five new compounds which are able to antagonize the effects of oestrogen in all tissues and species studied. The mechanism by which the pure anti-oestrogens produce their effects remains in question, but all of them are competitive antagonists of the oestrogen receptors and, moreover, have been proposed to block the shuttling of oestrogen receptors into the cell nucleus. When studied in vitro, these compounds are able to block the oestrogen-stimulated growth of breast cancer cells. In animals, their ability to block the effects of oestrogen on breast, uterus, bone, cardiovascular system and other reproductive-associated tissues has been demonstra…

Phytoestrogens increase the capacity of serum to stimulate prostacyclin release in human endothelial cells

Both the estrogen receptor (ER) alpha and beta isoforms are expressed in the endothelium. The ER beta has been assigned a crucial role in normal vascular wall function. Prostacyclin has been ascribed a beneficial effect on vessel wall physiology. Isoflavones bind with higher affinity to ER beta. We investigated the hypothesis that their administration to postmenopausal women can promote endothelial prostacyclin production.Twenty-five healthy postmenopausal women with mild climacteric symptoms received capsules containing 55 mg/day isoflavones derived from soy and red clover for 6 months. Cultured human umbilical vein endothelial cells (HUVECs) were exposed for 24 h to serum collected before…

Challenges and difficulties for a vice-principal for research

In the onset of our journey as a governing team, many feelings and ideas intermingle. In my case, as the new Vice-Principal for Research of the University of Valencia, I enthusiastically take on the responsibility of coordinating and facilitating the work of the researchers of the University of Valencia. Evidently, many challenges exist and resources are limited, but in recent years we have also managed to maintain and even increase research activity in science and humanities.

Impacto del metabolismo lipídico en la aterogénesis femenina

Resumen Objetivo Revisar los mecanismos que, ligados al metabolismo lipidico, determinan riesgo vascular en la mujer posmenopausica Fuentes Bibliografia medica hasta septiembre del ano 2000 a traves de MEDLINE Conclusiones Nuevos datos, ligados a la modificacion de particulas por oxidacion o cambios en su tamano, aclaran considerablemente la influencia de los lipidos en los procesos de aterogenesis

Endometrial response to concurrent treatment with vaginal progesterone and transdermal estradiol.

ABSTRACT Objective To describe the effect of the intermittent administration of vaginal progesterone and a low-dose estradiol patch on endometrial stability, as assessed by the rate of amenorrhea and endometrial stimulation. Methods This was an open study in which 64 moderately symptomatic, postmenopausal women were treated in the outpatient clinic of our University Hospital for different intervals up to 1 year. The treatment consisted of a combination of patches delivering 25 µg/day estradiol and intravaginal pills containing 100 mg of micronized progesterone. Patches and pills were administered concomitantly in a twice-a-week protocol. The endometrial response was assessed by endovaginal …

Sex differences in epigenetics mechanisms of cardiovascular disease

Abstract The role of sex in cardiovascular physiology has been extensively studied and has a great impact on the pathophysiology of cardiovascular diseases (CVD). In the last years, epigenetic regulation of gene expression has been established as a new mechanism for the correct cardiovascular homeostasis, involving both sex chromosomes and sex hormones. A number of epigenetic modifiers are encoded on sex chromosomes, which can induce sex differences in somatic gene expression independently of hormonal differences. Otherwise, sex hormones are transcriptional regulators in their own right by acting as ligands for nuclear hormone receptors and therefore providing the phenotype of sex-associate…

Estrogen receptor agonists and immune system in ovariectomized mice.

Several data implicate the immune system in bone lost after estrogen deficiency, however, some of the effects on the immune system of estrogen deficiency or of estrogen receptor (ER) modulation are not well established. In this study, the effect of ER agonists on the immune system in ovariectomized mice is analyzed. Mice were ovariectomized and were administered 17β-estradiol (E2), raloxifene (RAL) or genistein (GEN). The effect of a 4-week treatment on bone turnover and on several parameters that reflect the status of the immune system was studied. Results show that ovariectomy provoked both uterine atrophy and thymic hypertrophy. Although RAL corrected thymic hypertrophy, only E2 correct…

Progestogens stimulate prostacyclin production by human endothelial cells.

BACKGROUND: The effects of progestogens on endothelial physiology are poorly studied. Prostacyclin is a potent vasodilator synthesized by two isoforms of cyclooxygenase (COX) in endothelium. We examined the effects of two clinically used progestogens, progesterone and medroxyprogesterone acetate (MPA), on prostacyclin production by cultured human umbilical vein endothelial cells (HUVEC) and the possible role of progesterone receptors and both COX enzymes. METHODS: Cells were exposed to 1-100 nmol/l of either progesterone or MPA and prostacyclin production was measured in culture medium. RESULTS: Both progestogens significantly increased prostacyclin release in a time- and dose-dependent man…

Progestogens reduce thromboxane production by cultured human endothelial cells.

Objectives Progestogens have been poorly studied concerning their roles in endothelial physiology. Prostanoids are vasoactive compounds, such as thromboxane A2, a potent vasoconstrictor, and prostacyclin, a vasodilator. We examined the effects of two progestogens used clinically, progesterone and medroxyprogesterone acetate, on thromboxane A2 production by cultured human umbilical vein endothelial cells (HUVEC) and investigated the role of progesterone receptors and the enzymes involved in production of thromboxane A2 and prostacyclin. Methods Cells were exposed to 1‐100 nmol/l of either progesterone or medroxyprogesterone acetate, and thromboxane A2 production was measured in culture mediu…

Female Vascular Senescence

Long before the existence of cardiovascular imaging, Sir William Osler axiom that “man is as old as his arteries”. Followed by several physicians for decades, this aphorism has been widely confirmed by studies demonstrating that risk factors for cardiovascular disease increase as we age (Cooper et al., 1994; Lakatta & Levy, 2003). Nevertheless, a flaw in this statement is the generalization that men and women age similarly. Much data from clinical and basic research have established that vascular aging in women does not follow the same chronology as in men (Shaw et al., 2006; Pereira et al., 2010; Takenouchi et al., 2009). If known risk factors that influence cardiovascular aging are exclud…

Extracellular Histones Activate Endothelial NLRP3 Inflammasome and are Associated with a Severe Sepsis Phenotype

Jesús Beltrán-García,1– 3 Rebeca Osca-Verdegal,1,3 Daniel Pérez-Cremades,2,3 Susana Novella,2,3 Carlos Hermenegildo,2,3 Federico V Pallardó,1– 3 José Luis García-Giménez1– 3 1Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain; 2Instituto de Investigación Sanitaria INCLIVA, Valencia, Spain; 3Departamento de Fisiología, Facultad de Medicina y Odontología, Universitat de València, València, SpainCorrespondence: José Luis García-Giménez, Departamento de Fisiología, Facultad de Medicina y Odontología, Universitat de València, València, 46010, Spain, Tel +34 963 864 646, Email j.luis.garcia@uv.esIntrod…

Complete blockade of the vasorelaxant effects of Ang-(1-7) and bradykinin in murine microvessels by antagonists of the receptor Mas.

The heptapeptide angiotensin-(1-7) is a biologically active metabolite of angiotensin II, the predominant peptide of the renin-angiotensin system. Recently, we have shown that the receptor Mas is associated with angiotensin-(1-7)-induced signalling and mediates, at least in part, the vasodilatory properties of angiotensin-(1-7). However, it remained controversial whether an additional receptor could account for angiotensin-(1-7)-induced vasorelaxation. Here, we used two different angiotensin-(1-7) antagonists, A779 and d-Pro-angiotensin-(1-7), to address this question and also to study their influence on the vasodilatation induced by bradykinin. Isolated mesenteric microvessels from both wi…

Microparticles Harboring Sonic Hedgehog Morphogen Improve the Vasculogenesis Capacity of Endothelial Progenitor Cells Derived from Myocardial Infarction Patients.

Endothelial progenitor cells (EPC) play a role in endothelium integrity maintenance and regeneration. Decreased numbers of EPC or their impaired function correlates with an increase in cardiovascular events. Thus, EPC are important predictors of cardiovascular mortality and morbidity. Microparticles carrying Sonic hedgehog (Shh) morphogen (MPShhþ) trigger pro-angiogenic responses, both in endothelial cells and in ischaemic rodent models. Here, we propose that MPShhþ regulates EPC function, thus enhancing vasculogenesis, and correcting the defects in dysfunctional EPC obtained from acute myocardial infarction (AMI) patients.