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Methods of Endothelial Function Assessment International Journal of Cardiovascular Sciences. 2017;30(3):262-273 262 REVIEW ARTICLE Methods of Endothelial Function Assessment: Description and Applications Amanda Sampaio Storch, João Dario de Mattos, Renata Alves, Iuri dos Santos Galdino, Helena Naly Miguens Rocha Universidade Federal Fluminense, Niterói, Rio de Janeiro, RJ – Brazil Introduction molecule-1 (VCAM-1). These molecules are released in response to stimuli of inflammatory cytokines, The endothelium is a monolayer of cells, called bacterial lipopolysaccharides and oxidized low-density endothelial cells, that lines the interior of blood vessels, lipoproteins (ox-LDL). They promote cell-cell and 1 including arteries, veins and cardiac chambers, acting cell-extracellular matrix adhesion, leading to foam cell as a protective layer between circulating blood and other accumulation on the subendothelial space,8 increased 2 tissues. The endothelium is crucial for the control of vessel wall thickness and consequent reduction or even vascular homeostasis, and is involved in the regulation of complete obstruction of vascular lumen.9 intracellular signaling,1 vascular tonus and permeability,3 Assessment of endothelial function consists of the coagulation cascade and angiogenesis,4 among others. analysis of endothelial cells responsiveness to vasodilator One of the main activities of the endothelium is the or vasoconstrictor stimuli, contributing to advances in the release of autocrine and paracrine substances in response understanding of atherosclerosis and possible therapeutic to stimuli.2 Injuries to the endothelium trigger an targets.2 The methods include in vitro analysis, such as inflammatory response with participation of several culture of endothelial cells, and in vivo analysis, such cell types – lymphocytes, monocytes, platelets and smooth muscle cells5 – culminating in endothelial cell as flow-mediated dilation (FMD), venous occlusion dysfunction, stiffness of vessel wall and atherosclerotic plethysmography (VOP) and measurement of serum plaque formation.6 markers. However, none of these methods have been currently applied in the clinical setting, due to invasiveness, Endothelial dysfunction is an early, key characteristic high costs and difficult standardization of the techniques.1 of development and progression of atherosclerotic plaque and subsequent complications. This is characterized Endothelial dysfunction precedes morphological by a reduced bioavailability of endothelium-derived atherosclerotic changes and may contribute to the vasodilators, such as nitric oxide (NO), along with a development of lesions and clinical complications. relative or absolute increase in available vasoconstrictors. Cardiovascular diseases (CVD) are the main cause Such unbalanced condition impairs the endothelium- of natural death in the world, including in Brazil. dependent vasodilation, a functional marker of Recent data shows CVD accounted for approximately endothelial dysfunction.7 30% of deaths in the country. In this context, the use At the beginning of atherosclerotic plaque formation, of the aforementioned techniques in clinical research endothelial dysfunction is characterized by increased allows a better understanding of this problem and the expression and release of adhesion molecules, including development of new prevention and treatment strategies endothelial selectin (E-selectin), intercellular adhesion to decrease morbidity, mortality and also public costs. molecule-1 (ICAM-1) and vascular cell adhesion A deep understanding of endothelial dysfunction assessment tools by healthcare professionals allows the improvement of these techniques and enables the Keywords transition from clinical research to clinical practice. Endothelium, Vascular; Function, Endothelim; Here we describe the most recent methods for the Atherosclerosis; Vasodilatation. assessment of endothelial dysfunction. Mailing Address: Amanda Sampaio Storch Universidade Federal Fluminense - UFF Rua Professor Hernani Pires de Melo, 101 São Domingos, Niterói, RJ – Brazil E-mail: [email protected] DOI: 10.5935/2359-4802.20170034 Manuscript received August 15, 2016; revised November 21, 2016; accepted March 23, 2017. Storch et al. Int J Cardiovasc Sci. 2017;30(3):262-273 263 Methods for endothelial function assessment Review Article In vitro analysis Cultures of HUVECs are applied in studies on cell interactions (resulting in analysis of adhesion molecules and cytokines), effects of shear rate and oscillatory flow in Endothelial cell cultures cell signaling (mimicking what occurs in the vessel lumen), and allows the discovery of receptors and transcription Culture of endothelial cells has been widely factors involved in the development and progression of described in the literature, especially in studies on endothelial dysfunction.18-20 However, caution is needed the effect of oxidative stress and inflammation on in interpreting the results because of the limitations of mobilization and proliferation of these cells in vitro.1 this method. The yield of endothelial cells culture from peripheral blood represents an important step in research on circulating angiogenic cells, since these cells were In vitro functional studies firstly isolated for research purpose. In the last decades, different techniques have been However, the use of cell culture for assessment of used to assess endothelial function in vitro including the endothelial function has its pros and cons. The possibility organ bath technique, and myographic recordings, and of investigating a wide variety of intracellular signaling shown to be essential for the discovery of endothelium pathways allows the development of different studies, derived relaxing factors (EDRFs). The most widely with different purposes. For example, the discovery of studied EDRF is nitric oxide (NO).21 These studies allow surface markers, monoclonal antibodies, and magnetic the measurement of endothelium-dependent relaxation beads for immunoassays has facilitated the isolation, of vascular in response to well-known agonists, such as quantification and characterization of endothelial acetylcholine (ACh) and sodium nitroprusside.22 cells. However, this process has limitations related to Isolated organ bath is an in vitro technique that phenotypic changes of the cells, dependent on cell cuture assesses vascular reactivity in response to agonists, media and time. Also, the culture of endothelial cells has yielding a dose-response curve used to investigate not been fully established as a model comparable to in physiological and pharmacological responses of 10 vivo ones. Therefore, the protocol for cell culture should biological preparations isolated from a variety of species be carefully prepared, since many growing factors have (rabbit, rat, etc). Tissues and organs used in this method been recognized to stimulate different phenotypes in include artery and vein rings or strips, atrium, ventricle, 11 proliferating cells. papillary muscle, diaphragm, fundus of stomach, small Due to the difficulty in studying the endothelium in bowel (duodenum, jejunum, and ileum), trachea, uterus, vivo, several in vitro techniques have been developed.12 among others. The method aims to mimic an optimal Among these, human umbilical vein endothelial cells physiological condition regarding temperature, aeration (HUVECs) have been widely used as a source of human and nutrients for analysis of these preparations. An endothelial cells, since they are free from pathogens and organ bath system is composed of a double-jacketed are physiologically more relevant than other available glass chambers with capacity varying from 5 to 50mL lineages.13 Primary HUVECs preserve endothelial cell native connected to a helical warming coil through which the characteristics, including the expression of specific surface nutritive solution is conducted. The warming coil was markers and intracellular signaling pathways.14 submerged in water maintained at 37°C, which was In culture media, HUVECs change from a dispersed perfused with a peristaltic pump. The isolated organ or to a clustered pattern within days of incubation, covering tissue is maintained in muscle chamber; one end was most of the bottom surface of the plate.15 Once the plate attached to a glass rod connected to an air pump that is completed covered, the cells polarize, form tight provided aeration of the nutritive solution, and the other junctions, and finally achieve the cobblestone stage, end was fixed to a lever connected to a force transducer 23,24 which mimic the in vivo condition.16 HUVECs have by a cotton thread. been used in molecular biology research, contributing From this point on, the experiments have involved to advances in the pathophysiology of atheroma plaque the cumulative addition of drugs to the muscle formation and mechanisms involved in the control of chamber or electrical stimulation (when the organ was angiogenesis and vascularization of affected areas.12,17 mounted between to platinum electrodes connected Int J Cardiovasc Sci. 2017;30(3):262-273 Storch et al. Review Article Methods for endothelial function assessment 264 to an electrical stimulator), resulting in contraction or population and, for this reason, non-invasive methods relaxation of the muscle studied. Changes in tension are could be more practical and more accessible alternatives recorded by myographs (kymograph, physiography or for measurement of vascular function.27 1 digital system), that register the intensity and kinetics Among the non-invasive techniques for
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