Small extracellular vesicles from pregnant women with maternal supraphysiological hypercholesterolemia impair endothelial cell function in vitro.

Maternal physiological hypercholesterolemia MPH, maternal total cholesterol (TC) levels at term of pregnancy ≤280 mg/dL) occurs to assure fetal development. Maternal supraphysiological hypercholesterolemia (MSPH, TC levels >280 mg/dL) is a pathological condition associated with maternal, placental, and fetal endothelial dysfunction and early neonatal atherosclerosis development. Small extracellular vesicles (sEVs) are delivered to the extracellular space by different cells, where they modulate cell functions by transporting active signaling molecules, including proteins and miRNA. AIM: To determine whether sEVs from MSPH women could alter the function of endothelial cells (angiogenesis, endothelial activation and nitric oxide synthesis capacity). METHODS: This study included 24 Chilean women (12 MPH and 12 MSPH). sEVs were isolated from maternal plasma and characterized by sEV markers (CD9, Alix and HSP70), nanoparticle tracking analysis, transmission electron microscopy, and protein and cholesterol content. The endothelial cell line HMEC-1 was used to determine the uptake of labeled sEVs and the effects of sEVs on cell viability, endothelial tube formation, endothelial cell activation, and endothelial nitric oxide expression and function. RESULTS: In MSPH women, the plasma concentration of sEVs was increased compared to that in MPH women. MSPH-sEVs were highly taken up by HMEC-1 cells and reduced angiogenic capacity and the expression and activity of eNOS without changing cell viability or endothelial activation compared to MPH-sEVs. CONCLUSION: sEVs from MSPH women impair angiogenesis and nitric oxide synthesis in endothelial cells, which could contribute to MSPH-associated endothelial dysfunction.

Autophagy Process in Trophoblast Cells Invasion and Differentiation: Similitude and Differences With Cancer Cells.

Early human placental development begins with blastocyst implantation, then the trophoblast differentiates and originates the cells required for a proper fetal nutrition and placental implantation. Among them, extravillous trophoblast corresponds to a non-proliferating trophoblast highly invasive that allows the vascular remodeling which is essential for appropriate placental perfusion and to maintain the adequate fetal growth. This process involves different placental cell types as well as molecules that allow cell growth, cellular adhesion, tissular remodeling, and immune tolerance. Remarkably, some of the cellular processes required for proper placentation are common between placental and cancer cells to finally support tumor growth. Indeed, as in placentation trophoblasts invade and migrate, cancer cells invade and migrate to promote tumor metastasis. However, while these processes respond to a controlled program in trophoblasts, in cancer cells this regulation is lost. Interestingly, it has been shown that autophagy, a process responsible for the degradation of damaged proteins and organelles to maintain cellular homeostasis, is required for invasion of trophoblast cells and for vascular remodeling during placentation. In cancer cells, autophagy has a dual role, as it has been shown both as tumor promoter and inhibitor, depending on the stage and tumor considered. In this review, we summarized the similarities and differences between trophoblast cell invasion and cancer cell metastasis specifically evaluating the role of autophagy in both processes.

Cholesterol uptake and efflux are impaired in human trophoblast cells from pregnancies with maternal supraphysiological hypercholesterolemia.

Maternal physiological (MPH) or supraphysiological hypercholesterolaemia (MSPH) occurs during pregnancy. Cholesterol trafficking from maternal to foetal circulation requires the uptake of maternal LDL and HDL by syncytiotrophoblast and cholesterol efflux from this multinucleated tissue to ApoA-I and HDL. We aimed to determine the effects of MSPH on placental cholesterol trafficking. Placental tissue and primary human trophoblast (PHT) were isolated from pregnant women with total cholesterol <280 md/dL (MPH, n = 27) or ≥280 md/dL (MSPH, n = 28). The lipid profile in umbilical cord blood from MPH and MSPH neonates was similar. The abundance of LDL receptor (LDLR) and HDL receptor (SR-BI) was comparable between MSPH and MPH placentas. However, LDLR was localized mainly in the syncytiotrophoblast surface and was associated with reduced placental levels of its ligand ApoB. In PHT from MSPH, the uptake of LDL and HDL was lower compared to MPH, without changes in LDLR and reduced levels of SR-BI. Regarding cholesterol efflux, in MSPH placentas, the abundance of cholesterol transporter ABCA1 was increased, while ABCG1 and SR-BI were reduced. In PHT from MSPH, the cholesterol efflux to ApoA-I was increased and to HDL was reduced, along with reduced levels of ABCG1, compared to MPH. Inhibition of SR-BI did not change cholesterol efflux in PHT. The TC content in PHT was comparable in MPH and MSPH cells. However, free cholesterol was increased in MSPH cells. We conclude that MSPH alters the trafficking and content of cholesterol in placental trophoblasts, which could be associated with changes in the placenta-mediated maternal-to-foetal cholesterol trafficking.

Gestational Diabetes Mellitus Treatment Schemes Modify Maternal Plasma Cholesterol Levels Dependent to Women´s Weight: Possible Impact on Feto-Placental Vascular Function.

: Gestational diabetes mellitus (GDM) associates with fetal endothelial dysfunction (ED), which occurs independently of adequate glycemic control. Scarce information exists about the impact of different GDM therapeutic schemes on maternal dyslipidemia and obesity and their contribution to the development of fetal-ED. The aim of this study was to evaluate the effect of GDM-treatments on lipid levels in nonobese (N) and obese (O) pregnant women and the effect of maternal cholesterol levels in GDM-associated ED in the umbilical vein (UV). O-GDM women treated with diet showed decreased total cholesterol (TC) and low-density lipoproteins (LDL) levels with respect to N-GDM ones. Moreover, O-GDM women treated with diet in addition to insulin showed higher TC and LDL levels than N-GDM women. The maximum relaxation to calcitonin gene-related peptide of the UV rings was lower in the N-GDM group compared to the N one, and increased maternal levels of TC were associated with even lower dilation in the N-GDM group. We conclude that GDM-treatments modulate the TC and LDL levels depending on maternal weight. Additionally, increased TC levels worsen the GDM-associated ED of UV rings. This study suggests that it could be relevant to consider a specific GDM-treatment according to weight in order to prevent fetal-ED, as well as to consider the possible effects of maternal lipids during pregnancy.

Maternal Dyslipidaemia in Pregnancy with Gestational Diabetes Mellitus: Possible Impact on Foetoplacental Vascular Function and Lipoproteins in the Neonatal Circulation.

Dyslipidaemia occurs in pregnancy to secure foetal development. The mother shows a physiological increase in plasma total cholesterol and Triglycerides (TG) as pregnancy progresses (i.e. maternal physiological dyslipidaemia in pregnancy). However, in some women pregnancy-associated dyslipidaemia exceeds this physiological adaptation. The consequences of this condition on the developing fetus include endothelial dysfunction of the foetoplacental vasculature and development of foetal aortic atherosclerosis. Gestational Diabetes Mellitus (GDM) associates with abnormal function of the foetoplacental vasculature due to foetal hyperglycaemia and hyperinsulinaemia, and associates with development of cardiovascular disease in adulthood. Supraphysiological dyslipidaemia is also detected in GDM pregnancies. Although there are several studies showing the alteration in the maternal and neonatal lipid profile in GDM pregnancies, there are no studies addressing the effect of dyslipidaemia in the maternal and foetal vasculature. The literature reviewed suggests that dyslipidaemia in GDM pregnancy should be an additional factor contributing to worsen GDM-associated endothelial dysfunction by altering signalling pathways involving nitric oxide bioavailability and neonatal lipoproteins.

Vasodilator and hypotensive effects of pure compounds and hydroalcoholic extract of Xenophyllum poposum (Phil) V.A Funk (Compositae) on rats.

BACKGROUND: Xenophyllum poposum is an endemic species of the Andes Cordillera, popularly known as Popusa. Popusa is widely used by mountain communities as a folk medicine to treat altitude sickness and hypertension. PURPOSE: The aim of this study is to evaluate the hypotensive effects and vascular reactivity of Popusa extracts and its pure isolated compounds. METHODS: Hydroalcoholic extract of Xenophyllum poposum (HAE X. poposum; 40 mg/kg dose) were administered to rats by gavage and mean arterial pressures were recorded. Organ bath studies were conducted in endothelium-intact and denuded rings, and the vascular reactivity of the HAE X. poposum extract and its isolated compounds were compared and analysed. Cytosolic Ca2+ was measured in vascular smooth muscle cell line A7r5 using Fura2-AM. RESULTS: HAE X. poposum significantly reduced the mean arterial blood pressure and heart rate in normotensive rats chronically treated with the extract, as well as mice acutely treated with the extract. A negative chronotropic effect was observed in the isolated rat heart. HAE X. poposum induced endothelial vasodilation mediated by nitric oxide (NO), reduced the contractile response to PE, and decreased PE-induced intracellular Ca2+ influx in vascular smooth muscle cells. Pure compounds isolated from HAE X. poposum such as 4­hydroxy­3-(3-methyl-2-butenyl) acetophenone, 5-acetyl-6­hydroxy­2-isopropenyl-2, and 3-dihydrobenzofurane (dihydroeuparin) also triggered endothelium-dependent vasodilation. CONCLUSION: HAE X. poposum decreases blood pressure, heart rate and vascular response. The vasodilation properties of HAE X. poposum extract and its isolated compounds may act through the endothelial nitric oxide synthase, as well as calcium channel blocker mechanisms. The results of the present study provide the first qualitative analysis that supports the use of X. poposum in traditional folk medicine for the treatment of altitude sickness and hypertension.

Maternal supraphysiological hypercholesterolemia associates with endothelial dysfunction of the placental microvasculature.

Maternal physiological or supraphysiological hypercholesterolemia (MPH, MSPH) occurs during pregnancy. MSPH is associated with foetal endothelial dysfunction and atherosclerosis. However, the potential effects of MSPH on placental microvasculature are unknown. The aim of this study was to determine whether MSPH alters endothelial function in the placental microvasculature both ex vivo in venules and arterioles from the placental villi and in vitro in primary cultures of placental microvascular endothelial cells (hPMEC). Total cholesterol < 280 mg/dL indicated MPH, and total cholesterol ≥280 mg/dL indicated MSPH. The maximal relaxation to histamine, calcitonin gene-related peptide and adenosine was reduced in MSPH venule and arteriole rings. In hPMEC from MSPH placentas, nitric oxide synthase (NOS) activity and L-arginine transport were reduced without changes in arginase activity or the protein levels of endothelial NOS (eNOS), human cationic amino acid 1 (hCAT-1), hCAT-2A/B or arginase II compared with hPMEC from MPH placentas. In addition, it was shown that adenosine acts as a vasodilator of the placental microvasculature and that NOS is active in hPMEC. We conclude that MSPH alters placental microvascular endothelial function via a NOS/L-arginine imbalance. This work also reinforces the concept that placental endothelial cells from the macro- and microvasculature respond differentially to the same pathological condition.

Adenosine receptors: Modulators of lipid availability that are controlled by lipid levels.

Adenosine as well as agonists and antagonists for the four adenosine receptor subtypes (A1R, A2AR, A2BR and A3R) play a role in several key physiological and pathophysiological processes, including the regulation of vascular tone, thrombosis, immune response, inflammation, and angiogenesis. This review focuses on the adenosine-mediated regulation of lipid availability in the cell and in the systemic circulation as well in humans and animal models. Therefore, adenosine, mainly by acting on A1R, inhibits lipolysis activity, leading to reduction of the circulating fatty acid levels. This nucleoside can also participate in the early development of atherosclerosis by inhibiting the formation of foam cells via stimulation of cholesterol efflux through A2AR expressed on macrophages and reduction of the inflammatory process by activating A2AR and A2BR. Adenosine also appears to modulate intracellular cholesterol availability in Niemann-Pick type C1 disease and Alzheimer disease via A2AR and A3, respectively. Remarkably, the role of adenosine receptors in the regulation of plasma total cholesterol and triglyceride levels has been studied in animal models. Thus, an anti-atherogenic role for A2BR as well as a pro-atherogenic role of A2AR and A1 have been proposed; A3R has not been shown to participate in the control of lipid levels or the development of atherosclerosis. Surprisingly, and despite the role of A2A in the inhibition of foam cell formation among isolated cells, this receptor appears to be pro-atherogenic in mice. Remarkably, the role of adenosine receptors in human dyslipidaemia and atherosclerosis must to be elucidated. Additionally, it has been reported that increased lipid levels impair the effects of adenosine/adenosine receptors in controlling vascular tone, and we speculate on the possibility that this impairment could be due to alterations in the composition of the membrane microdomains where the adenosine receptors are located. Finally, a possible role for adenosine/adenosine receptors in the phenomena of dyslipidaemia in pregnancy has been proposed.

Hypotensive and antihypertensive effects of a hydroalcoholic extract from Senecio nutans Sch. Bip. (Compositae) in mice: Chronotropic and negative inotropic effect, a nifedipine-like action.

ETHNOPHARMACOLOGICAL RELEVANCE: Senecio nutans Sch. Bip. (Compositae) is an endemic plant of South America used in the management of acute mountain sickness in the Andean communities. Currently, the direct effects of hydroalcoholic extract from S. nutans on the cardiovascular system are unknown. The aim of this study was to determine the effects and mechanism of action of S. nutans on cardiovascular function in normotensive and Angiotensin II (1µg/mL) hypertension mice models. MATERIAL AND METHODS: Blood pressure and ECG measurements were simultaneously carried out on the mice and rats. The isolated right atrium, papillary muscle of the left ventricle and isolated heart of rat were used to study the cardiac functions and mechanisms. RESULTS: S. nutans (40mg/Kg) induced a 30% and 12% significant (p<0.05) reduction of the mean arterial pressure (MAP) in normotensive and hypertensive mice respectively. This decrease was as a result of decrease in heart rate (HR) in normotensive (25%) and hypertensive model (31%). It also decreased the sinus rhythm in isolated right atrium of rat. Compared with Losartan, a known anti-hypertensive, S. nutans caused a dose-dependent negative inotropic effect (dP/dtmax) on Langendorff isolated heart system. While Losartan, decreased the MAP by 30% but had no effect on heart rate. The calcium blocker nifedipine had similar effects as S. nutans, decreasing the beat frequency of isolated right atrium and contractility of papillary muscle of the left ventricle of rat. CONCLUSION: The results suggest an important clinical function in hypertension therapy, as S. nutans could decrease the blood pressure in hypertensive mice by decreasing the HR and contractility, leading to a reduction in myocardial oxygen demand.

Conocimientos, actitudes y prácticas de cuidadores de personas con discapacidad, en procesos de inclusión social en el municipio Madrid, Cundinamarca, Colombia / Knowledge, Attitudes and Practices of Caregivers of People with Disabilities in Processes of Social Inclusion in the Municipality of Madrid, Cundinamarca, Colombia / Conhecimentos, atitudes e práticas de cuidadores de pessoas com deficiência em processos de inclusão social no município Madrid, Cundinamarca, Colombia

Introducción: La inclusión social de personas con discapacidad (PCD) depende de múltiples factores económicos, sociales, políticos y culturales, que afectan su desarrollo social. Uno de los factores que genera mayor exclusión social, corresponde a las barreras actitudinales que se identifican en el entorno cercano. Objetivo: Identificar conocimientos, actitudes y prácticas de cuidadores primarios, acerca de la discapacidad y el cuidado que ofrecen a las PCD vinculadas a los servicios del Centro Ambulatorio Gustavo Escallón Cayzedo de la Fundación Santa Fe de Bogotá (CAGEC), en el municipio de Madrid, Cundinamarca. Materiales y métodos: Investigación con enfoque mixto, estudio descriptivo, dirigido a cuidadores de PCD, a quienes se les realizó una entrevista semiestructurada. El análisis cuantitativo se realizó mediante estadística descriptiva y el análisis cualitativo se realizó generando una matriz de categorías establecidas y emergentes. Resultados: Se evidencian condiciones económicas y laborales que afectan de manera importante la vida de los cuidadores, quienes dedican más de diez horas al día al cuidado de la PCD, lo que genera en algunos síntomas del "síndrome del cuidador". La mayoría de los cuidadores no conocen los derechos y deberes de la población, y aquellos que los conocen lo asocian con el acceso a servicios. La participación se asocia con asistencia a ciertas actividades, no desde su noción política. Estos conocimientos se relacionan con las prácticas de los cuidadores, que se orientan bajo el modelo biomédico. Discusión: Al ser estudiadas las condiciones del cuidador desde las barreras, actitudes y las redes de apoyo, se observa cómo estas afectan su proyecto de vida. A pesar de esta situación, las actividades de las entidades públicas y privadas se dirigen a las PCD, por lo que se sugiere la realización de acciones que promuevan la salud del cuidador.

Introduction: Social inclusion of people with disabilities (pwd) depends on many economic, social, political and cultural factors that affect their social development. One factor that generates greater social exclusion corresponds to attitudinal barriers identified in the immediate environment. Objective: To identify knowledge, attitudes and practices of primary caregivers, about disability and care they provide to PCD linked to services of the Outpatient Center Gustavo Escallon Cayzedo of the Fundacion Santa Fe de Bogota Foundation -CAGEC-, in the municipality of Madrid, Cundinamarca. Material and methods: Research with mixed approach, descriptive study aimed at caregivers of pwd, to whom a semi-structured interview was applied. The quantitative analysis was performed using descriptive statistics and qualitative analysis was performed by generating an array of established and emerging categories. Results: Economic and labor conditions significantly affect the lives of caregivers, who spend more than ten hours a day to assist pwd, evidently resulting in some symptoms of the "caregiver syndrome". Most caregivers do not know the rights and duties of the population, and those who do know them, come to associate them with the access to services. Participation is connected with assisting to certain activities, rather than with its political notion. These skills relate to caregiver practices that are oriented to the biomedical model. Discussion: Having studied the conditions of the caregiver barriers, attitudes and support networks, the way these affect their life projects is observed. Despite this, the activities of public and private instances are only directed to the pwd; therefore, the implementation of actions that promote the caregiver's health is suggested.

A inclusão social de pessoas com deficiência (PCD), dependem de múltiplos fatores económicos, sociais,políticos e culturais, que afetam seu desenvolvimento social. Um dos fatores que gera maior exclusão social, corresponde a barreiras atitudinais que identificam-se no entorno próximo. Objetivos: Identificar conhecimentos, atitudes e práticas de cuidadores primários, acerca da deficiência e o cuidado que oferecem a PCD vinculadas aos serviços do Centro Ambulatório Gustavo Escallón Cayzedo da Fundación Santa Fé de Bogotá (CAGEC), município de Madrid, Cundinmarca. Materiais e métodos: pesquisa com enfoque misto, estudo descritivo, dirigido a cuidadores de PCD, a quem se aplicou uma entrevista semiestruturada. A análise quantitativa se realizou mediante estadística descritiva e a análise qualitativa realizou-se gerando uma matriz de categorias estabelecidas e emergentes. Resultados: se evidenciam condições económicas e laborais que afetam de maneira importante a vida dos cuidadores, que dedicam mais de 10 horas no dia ao cuidado da PCD, gerando em alguns sintomas da "síndrome do cuidador". A maioria dos cuidadores não conhecem os direitos e deveres da população, e aqueles que os conhecem o associam com o acesso a serviços. A participação se associa com assistência a certas atividades, e não desde sua noção política. Estes conhecimentos se relacionam com as práticas dos cuidadores as quais orientam-se sob o modelo biomédico. Discussão: ao ser estudadas as condições do cuidador desde as barreiras, atitudes e as redes de apoio, observa-se como estas afetam seu projeto de vida. Apesar desta situação, as atividades das entidades públicas e privadas dirigem-se à PCD, pelo que se sugere a realização de ações que promovam a saúde do cuidador.

Manejo de la pareja esteril en Quito: un año de experiencia / Management of the sterile couple in Quito: 1-year experience

Entre Marzo de 1984 a Febrero de 1985, en el Instituto de Reproducción Humana de Quito, se estudiaron bajo un protocolo definido a 20 parejas estériles y 4 infértiles. En las estériles los factores etiológicos fueron anovulación crónica 7 casos (35%), tubo-peritoneal-uterino 7 casos (35%), masculino 5 (25%); imunológico 5 casos (25%), psicológico 2 casos (10%) y coital 1 caso (5%). El porcentaje de éxito en esta serie, entendido por embarazo con recién nacido vivo, fue del 30% (6 casos) en parejas estériles y del 75% (3 casos) en infértiles. En las 6 parejas estériles en las que se obtuvo éxito, dos fueron tratadas con clomifeno, con Psicoterapia 2 parejas, con Inseminación Artificial Heteróloga una paciente y con hormona específica para hipotiroidismo la restante. Las parejas infértiles representaron un esquema especial de estudio y tratamiento, de los 3 casos exitosos, uno fue con hormona tiroidea, otro con 17 alfa hidroxiprogesterona y el tercero con ceclaje cervical