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The endothelium: A primer

The endothelium: A primer
Literature review current through: Jan 2024.
This topic last updated: Oct 13, 2023.

INTRODUCTION — Endothelial cells (ECs) form the lining of all blood and lymphatic vessels within the vascular tree. The adult human body contains at least one trillion endothelial cells, which weigh more than 100 g and cover a surface area of more than 3000 square meters [1,2]. They therefore constitute a distributed organ that forms a dynamic interface with all other organs in the body.

The endothelium mediates vasomotor tone, regulates cellular and nutrient trafficking, maintains blood fluidity, contributes to the local balance between pro- and anti-inflammatory mediators as well as procoagulant and anticoagulant activity, participates in generation of new blood vessels, orchestrates organ development, participates in innate and acquired immunity, interacts with circulating blood cells, and undergoes programmed cell death [3,4]. Each of these activities is dynamically regulated in both space and time. Because endothelial cells receive cues from a wide variety of cells and tissues, they possess disparate properties that are specific to their local environment. Other phenotypic differences between endothelial cells are "locked in" by site-specific epigenetic mechanisms. Phenotypic heterogeneity is a central feature of the endothelium, and includes variations in morphology, biosynthetic repertoire, and behavior [5].

Here we review some of the general features of the endothelium [6].

Disease-specific considerations, which are presented separately, include:

The cardiovascular system – (See "Coronary endothelial dysfunction: Clinical aspects".)

Pulmonary disorders – (See "The epidemiology and pathogenesis of pulmonary arterial hypertension (Group 1)" and "Inhaled nitric oxide in adults: Biology and indications for use", section on 'Biology and pharmacokinetics' and "Acute respiratory distress syndrome: Epidemiology, pathophysiology, pathology, and etiology in adults" and "Transfusion-related acute lung injury (TRALI)", section on 'Pathogenesis'.)

Malignancy – (See "Overview of angiogenesis inhibitors".)

Diabetes – (See "Diabetic retinopathy: Pathogenesis", section on 'Growth factors'.)

Obstetrical disorders – (See "Preeclampsia: Pathogenesis", section on 'Role of systemic endothelial dysfunction in clinical findings'.)

Infection – (See "Pathophysiology of sepsis", section on 'Circulation' and "Pathogenesis of hantavirus infections", section on 'Tissue tropism'.)

Hematology – (See "Pathophysiology of sickle cell disease", section on 'Adhesion of sickled cells to the vascular endothelium' and "Pathophysiology of TTP and other primary thrombotic microangiopathies (TMAs)" and "Pathophysiology of von Willebrand disease", section on 'Bridging between platelets and vascular subendothelium'.)

Hepatology – (See "Hepatic sinusoidal obstruction syndrome (veno-occlusive disease) in adults", section on 'Pathogenesis'.)

Neurology – (See "Cerebrospinal fluid: Physiology and utility of an examination in disease states", section on 'Microbe entry in meningitis'.)

THE ENDOTHELIUM FROM BENCH TO BEDSIDE — Human endothelial cells were first propagated in culture in the early 1970s [7]. Although there have been major subsequent advances in our understanding of endothelial cell (EC) biology based upon this critically important technology, it is still apparent that ECs tend to dedifferentiate and lose their specialized characteristics in culture.

In past decades, limitations to studying ECs in vivo have included the absence of effective imaging techniques, the dearth of suitable biomarkers reflecting their biologic behavior, and their distinct structural and functional heterogeneity.

Subsequently, single cell multiomic analyses of capillary ECs have revealed precise profiles in gene expression and chromatin accessibility [8]. Such gene expression profiles can explain cellular architecture, tissue-specific signaling, and metabolic pathways, and they have identified marker genes associated with organ-specific vascular subtypes. New multiomic EC atlases will likely pave the way for targeted EC therapies as well as the rational design of organ-specific vascular networks for tissue engineering and possibly organ replacement.

ENDOTHELIAL HETEROGENEITY

Complex signaling patterns — Endothelial cells (ECs) receive and respond to signals from both surrounding cells and tissues, and flowing blood. Afferent signals are provided by soluble mediators, cell contacts, changes in oxygenation, hemodynamic forces, temperature, and pH. Efferent responses modulate vasomotor tone, vascular permeability, hemostatic balance, inflammatory signals, as well as cellular proliferation and survival. The response of the EC to a given stimulus may vary dramatically from one vascular bed to another, over time, and depending on environmental stimuli [9].

Structural specializations — In different vascular beds, ECs develop discrete ultrastructural specializations [10]. In the central nervous system, for example, the endothelium is "continuous" with complex tight junctions that form the blood-brain barrier. ECs in the endocrine glands and renal glomeruli are "fenestrated," with transcellular pores that permit hormone protein secretion and plasma filtration. ECs that allow the exchange of cells or particles are "discontinuous", displaying gaps between adjacent cells and poorly formed underlying basement membrane; these cells typify sinusoids of the liver, spleen, and bone marrow.

Temporal variations — In a given vascular bed, EC properties differ from one moment to the next as they respond to physiologic and pathophysiologic stimuli [11-14]. Both spatial and temporal heterogeneity contribute to the frequently focal nature of vasculopathic disease states.

Changing synthetic repertoires — Advances in genomics and proteomics have uncovered an expansive array of site-specific properties of the endothelium [15-18]. These characteristics reflect differences in programs of protein synthesis, and result from specific signals that originate in the surrounding cells and tissues.

The following three examples show how this variability may be clinically relevant:

Anatomic variation – The procoagulant/anticoagulant balance appears to differ between the endothelium of the venous valvular sinus and vein lumen, with the valvular sinus endothelium displaying decreased expression of von Willebrand factor [19].

Vascular bed variation – In patients with thrombotic thrombocytopenic purpura (TTP), differences in vascular endothelial damage might reflect the fact that CD36, the thrombospondin receptor, is found on human microvascular ECs (HMVEC), but not ECs of large (umbilical) vessels (HUVEC). (See "Pathophysiology of TTP and other primary thrombotic microangiopathies (TMAs)", section on 'Histopathology of TMA'.)

Temporal variation – In a transgenic mouse model of sickle cell disease (SCD), EC expression of tissue factor was confined almost exclusively to the pulmonary veins [20]. This expression increased significantly following exposure of the mild SCD mouse models to one cycle of hypoxia/reoxygenation, converting the phenotype to that of the severe SCD mouse.

PATTERNS OF CHANGE IN ENDOTHELIAL FUNCTION

EC activation — Originally, the term "endothelial cell activation" was based on the observation that cultured endothelial cells (ECs) demonstrated increased leukocyte adhesion following exposure to inflammatory mediators. The term was expanded later to embrace a wider spectrum of phenotypic changes, including decreased thromboresistance, altered vasomotor tone, and loss of barrier function. According to this paradigm, quiescent ECs display a thromboresistant, anti-adhesive and vasodilatory phenotype, whereas activated ECs have procoagulant, pro-adhesive, and vasoconstricting properties.

However, to avoid oversimplification with regard to the state of EC activation, it is important to remember the following points:

The phenotypic spectrum of ECs is a dynamic continuum.

Activation for one type of EC may not meet the definition of activation at another site. For example, non-inflamed skin venules express P-selectin constitutively [21], whereas venules from other sites (eg, the mesentery) express P-selectin only when activated.

Inflammatory mediators such as tumor necrosis factor-alpha, thrombin, and lipopolysaccharide may have distinct or only partially overlapping effects on EC phenotypes [22].

EC activation is not an all-or-nothing response, nor is it necessarily linked to disease. Normal endothelium is highly responsive to alterations in the local extracellular milieu. Such environmental changes might occur in the setting of transient bacteremia, minor trauma, and other common stresses (eg, small temperature changes, proteolytic activity, and shear stress), and can be transient and mild or sustained and severe.

EC dysfunction — EC dysfunction, broadly understood, is a feature of the aging vasculature [23]. Initially, EC dysfunction referred to EC structural changes, loss of integrity, or hyper-adhesiveness of the vascular lining toward platelets as might be seen in atherosclerosis [24-26]. Over time, the term came to reflect the loss of the endothelium's ability to regulate vascular resistance. More recently, the term EC dysfunction has been broadly applied to states in which the EC phenotype, whether or not it meets the definition of activation, poses a net liability to the host. Examples include severe sepsis (see 'Severe sepsis' below), pulmonary hypertension, pathological angiogenesis, thrombotic thrombocytopenic purpura, hepatic veno-occlusive disease, and sickle cell disease.

Nitric oxide production — The principal physiologic stimulus for endothelial nitric oxide (NO) synthesis is blood flow-induced shear stress, a process termed "flow-mediated vasodilatation" (see "Coronary artery endothelial dysfunction: Basic concepts", section on 'Nitric oxide function'). In addition, a variety of agonists, including acetylcholine, histamine, thrombin, serotonin, adenosine diphosphate, bradykinin, and norepinephrine, can increase the synthesis and release of NO. These agonists result in vasorelaxation when the endothelium is intact, and vasoconstriction if the endothelium is removed or perturbed.

NO has a number of other effects. It inhibits platelet adhesion and aggregation, an effect that may be synergistic with that of prostacyclin. NO blocks monocyte adhesion to the endothelium. NO also reduces endotoxin- and cytokine-induced expression of tissue factor, thus modulating the prothrombotic potential of the endothelial cell.

Paradoxical vasoconstriction of coronary arteries induced by acetylcholine was described in early and advanced human atherosclerosis. The current belief is that an abnormal vascular response to acetylcholine may represent a defect in EC vasodilator function, due at least in part to reduced EC production of NO [27].

Leukocyte adhesion to endothelium — A pathophysiologic link has been made between inducible endothelial-leukocyte adhesion molecules and atherosclerosis (so-called athero-ELAMs) via the identification of an inducible endothelial cell-specific antigen that binds predominantly to monocytes [28]. Peptide sequencing revealed homology to the predicted sequence of human vascular cell adhesion molecule (VCAM)-1, which had been previously cloned as a cytokine-inducible protein in endothelial cells [29]. Subsequently, VCAM-1 was localized to the endothelium overlying atherosclerotic lesions in a hyperlipidemic rabbit model [28] and was shown to be a risk factor for venous thrombosis in a kindred with protein C deficiency [30]. These observations not only emphasized the role of endothelial dysfunction as a primary determinant of atherosclerosis, but also helped to refocus research and development on the inflammatory nature of this disease process.

Additional details regarding leukocyte-endothelial interactions in the pathogenesis of inflammation are presented separately. (See "Leukocyte-endothelial adhesion in the pathogenesis of inflammation".)

Interactions with the hemostatic system — ECs produce a wide array of thromboregulators that act at both early and late stages of thrombus formation [31].

Early regulators include the endothelial eicosanoid prostacyclin (PGI2) and nitric oxide, both of which inhibit platelet reactivity and induce vascular relaxation, and extracellular adenosine triphosphate diphosphohydrolase (ectoADPase-1), which prevents further platelet recruitment. (See "Overview of hemostasis", section on 'Formation of the platelet plug'.)

Late acting thromboregulators include natural anticoagulants such as antithrombin, which inhibits thrombin and factor Xa; tissue factor pathway inhibitor (TFPI), which blocks complex formation between factor VIIa and tissue factor; and the thrombomodulin/endothelial cell protein C receptor (EPCR)/protein C system, which inactivates procoagulant factors. (See "Overview of hemostasis", section on 'Control mechanisms and termination of clotting'.)

Endothelial cells are associated with the fibrinolytic system, as they synthesize and secrete tissue plasminogen activator (tPA) and assemble plasmin forming molecules through expression of key receptors on their surface, such as the annexin A2 complex. Deficiency of annexin A2 was associated with increased incidence of venous thromboembolic disease in one study [32]. (See "Overview of hemostasis", section on 'Clot dissolution and fibrinolysis'.)

COVID-19 AND ENDOTHELIAL INJURY — Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, is a multisystem inflammatory disease [33-35] characterized by increasingly severe hypoxia, pulmonary vascular leak, cytokine storm, and multiorgan failure, especially in individuals with pre-existing vascular injury associated with diabetes, hypertension, atherosclerosis, or a history of smoking [33-35].

In severe COVID-19, microvascular thromboinflammation and potentially catastrophic macrovascular venous thromboembolism can occur, involving lungs, kidneys, heart, and other organs [36]. Autopsy reports indicate a pauci-inflammatory capillary injury, also referred to as endotheliitis, with fibrin deposition and activation of terminal components of complement, including C5b-9, C4b, and mannose-binding lectin-associated serine [37-39]. Endothelial injury is one of the three major contributors to hypercoagulability. (See "COVID-19: Hypercoagulability", section on 'Virchow's triad'.)

SEPSIS AS A MODEL ENDOTHELIOPATHY — Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection [40]. Sepsis is a common and often fatal disorder in which changes in endothelial function play a central role [41,42]. The assault on the endothelium occurs on three separate fronts [43]:

Pathogens may directly infect endothelial cells (ECs) [44].

Components of the bacterial cell wall (eg, lipopolysaccharide [LPS]) may activate pattern recognition receptors on the surface of the EC [45-48].

Host-derived products (eg, complement, cytokines, chemokines, serine proteases, fibrin, activated platelets and leukocytes, elevated glucose, reactive oxygen species or hypoxia-induced factors, and hemodynamic changes) may activate ECs [49].

The endothelium responds to these stresses in ways that differ according to the nature of the pathogen, host genetics, underlying comorbidity, age, sex, and the location of the vascular bed. These responses may include structural changes, such as nuclear vacuolization, cytoplasmic swelling, cytoplasmic fragmentation, denudation, and/or detachment [50]. However, functional changes in the endothelium are even more common and include shifts in hemostatic balance, increased leukocyte adhesion and trafficking, altered vasomotor tone, loss of barrier function, and programmed cell death.

Procoagulant properties — Inflammatory mediators may interact with ECs to induce a loss of the normal thromboresistant phenotype. In cultured endothelial cells, addition of bacterial lipopolysaccharide and/or cytokines results in a series of procoagulant responses [41,42] including decreased synthesis of thrombomodulin (TM), tissue-type plasminogen activator and heparan sulfate, increased expression of tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1), and generation of procoagulant microparticles [51]. (See 'Interactions with the hemostatic system' above.)

In whole animal models of sepsis, however, the endothelium does not express detectable TF with the possible exception of the spleen and aorta [52,53]. Moreover, while the association of sepsis and decreased levels of TM has been confirmed in the skin vasculature [54], this phenomenon does not apply to all vascular beds. ECs of the blood brain barrier, for example, do not normally express TM [55].

In vivo, properties of ECs that may contribute to the sepsis-associated procoagulant state include recruitment of platelets, monocytes, and neutrophils, all of which are capable of initiating or amplifying coagulation; cell surface translocation of anionic phospholipids that enhance the binding of coagulation complexes; increased exposure of subendothelium (eg, collagen, fibronectin, fibrinogen, von Willebrand factor), which may serve as attachment sites for platelets as ECs undergo apoptosis [56,57]; and development of a low flow state, as a result of reduced cardiac output, vasoconstriction, or occlusive lesions, leading to reduced clearance of activated procoagulant serine proteases, thus promoting additional clotting.

Evidence that increased endothelial cell anticoagulant activity can reverse the coagulopathy associated with LPS administration comes from a transgenic mouse model. When either the leech anticoagulant hirudin or human tissue factor pathway inhibitor (TFPI) was expressed on endothelial cells, monocytes, and platelets, widespread intravascular thrombosis, thrombocytopenia, and coagulopathy were inhibited [58]. While it does not describe a clinically-relevant approach, this study supports the postulate that modulation of endothelial cell properties can modify the clinical expression of endotoxemia.

Disseminated intravascular coagulation — Virtually all patients with severe sepsis have activation of the coagulation cascade. Initiation of clotting is thought to reflect expression of tissue factor on the surface of activated monocytes and macrophages, with subsequent induction of increased thrombin generation, and fibrin formation. In the extreme, this leads to depletion of coagulation factors, disseminated intravascular coagulation (DIC), and possible end-organ damage. (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults".)

The extent to which the above changes occur in the intact endothelium is not entirely clear. As with other properties of the endothelium, the hemostatic balance is differentially regulated among the various vascular beds. In a baboon sepsis model, for example, administration of lethal doses of E. coli resulted in increased fibrin deposition in the marginal zone and sinusoids of the spleen, hepatic sinusoids, glomeruli, and peritubular vessels of the kidney, but little or no fibrin in the portal vessels of the liver, cerebral cortex, skin, myocardium, or aorta [52]. These results, and similar data obtained in mouse models of sepsis, point to a predilection for organ-specific coagulation in sepsis. Their clinical relevance is supported by studies of cerebral malaria in which malaria-associated depletion of endothelial protein C receptor (EPCR), with subsequent impairment of the protein C system, promotes a proinflammatory, procoagulant state in brain microvessels [59].

Genetic influences — In mice with genetically determined hypercoagulable states, sepsis results in a marked shift in hemostatic balance in ways that differ between vascular beds. For example, in mice that carry a thrombomodulin (TM) gene mutation, disruption of the TM-dependent activation of protein C via the administration of lipopolysaccharide (LPS) resulted in higher levels of fibrin deposition in the lung and kidney, but not the brain, compared with wild-type mice [60]. In contrast, in heterozygous antithrombin-deficient mice, LPS challenge resulted in increased deposition of fibrin in the kidney, liver, and heart [61]. These studies demonstrate the importance of underlying genetics in the sepsis phenotype. (See "Overview of hemostasis", section on 'Activated protein C and protein S'.)

Pro-adhesive properties — In some endothelia, inflammatory mediators induce expression of adhesion molecules such as P-selectin [62], E-selectin, intercellular adhesion molecule (ICAM)-1, and vascular cell adhesion molecule (VCAM)-1. These alterations are particularly prominent on post-capillary venules [63,64], and result in increased rolling, adherence, and transmigration of leukocytes into underlying tissue. (See "Leukocyte-endothelial adhesion in the pathogenesis of inflammation".)

Activated ECs also recruit increased numbers of platelets to the blood vessel wall. This process may contribute to vaso-occlusive crises in patients with sickle cell disease by promoting adhesion of red cells. (See "Pathophysiology of sickle cell disease", section on 'Adhesion of sickled cells to the vascular endothelium'.)

Similarly, upregulation of platelet activating factor (PAF) receptors on chronically activated ECs may predispose patients with sickle cell disease to invasive pneumococcal infection. (See "Streptococcus pneumoniae: Microbiology and pathogenesis of infection", section on 'Invasion'.)

Vasomotor properties — Vasomotor tone is regulated through a combination of endothelial-dependent and -independent mechanisms. ECs produce vasoactive molecules that regulate arteriolar tone and contribute to blood pressure control. These factors include both vasodilators (eg, nitric oxide [NO], prostacyclin) and vasoconstrictors (eg, endothelin, thromboxane A2, and platelet-activating factor). (See "Inhaled nitric oxide in adults: Biology and indications for use".)

NO levels are elevated during sepsis and appear to play a complex role in the associated vascular pathology [65,66]. It has been suggested that red blood cells may directly mediate systemic vascular relaxation and hypotension in sepsis through NO-dependent mechanisms [67]. (See "Structure and function of normal hemoglobins", section on 'Nitric oxide transport'.)

Increased permeability — In the intact vasculature, the endothelium forms a continuous, semipermeable barrier that varies in integrity in different vascular beds. A central feature of the endothelium in sepsis is its increased permeability and loss of barrier function, resulting in extravasation of circulating elements and tissue edema [68]. Several proteins contribute to this phenomenon:

Tumor necrosis factor (TNF)-alpha induces an increase in EC permeability both in vitro and in vivo.

Thrombin increases EC permeability in vivo, while TNF-alpha and thrombin act synergistically to induce barrier dysfunction in vitro.

Vascular endothelial growth factor (VEGF), which is produced by several different cell types, acts on vascular endothelial cells to stimulate angiogenesis. VEGF induces EC proliferation, survival and directed migration, while it also increases vascular permeability. VEGF is 50,000 times more potent in inducing vascular leakage than histamine. VEGF levels are elevated in sepsis, and VEGF has been shown to play a pathogenic role in mouse models of sepsis [69]. (See "Overview of angiogenesis inhibitors", section on 'Vascular endothelial growth factor'.)

Angiopoietin 2 (ANGPT2), which is rapidly released from Weibel-Palade bodies in states of inflammation, attenuates Tie-2 signaling in endothelial cells, resulting in enhanced barrier disruption. ANGPT2 levels are elevated during sepsis and have been shown to predict development of shock and death [70,71].

Glycocalyx, a major proteoglycan-containing constituent of the endothelial surface layer that limits the access of cells and solutes to the surface of the endothelium and contributes to cell signaling, may become degraded in sepsis, leading to increased permeability [72,73].

Endothelial junction proteins such as vascular endothelial cadherin (VE-cadherin), vascular endothelial protein tyrosine phosphatase, and Src-homology phosphatase 2 (SHP2) regulate adherens-like inter-endothelial junctions. In the lung, but not in other tissues, annexin A2 promotes microvascular integrity by enabling dephosphorylation of VE-cadherin [74].

Annexin A2 is a membrane-binding protein that recruits key phosphatases to endothelial-endothelial cell junctions formed by homotypic VE-cadherin interactions. VE-protein tyrosine phosphatase and Src homology phosphatase prevent over-phosphorylation of VE-cadherin, thereby maintaining closed inter-endothelial junctions and preventing vascular leak under hypoxia. This mechanism is active primarily in the lung but not in other organ microvascular beds [74].

EC apoptosis — Normally, less than 0.1 percent of all ECs are apoptotic. However, certain pathogens are capable of inducing EC apoptosis in vitro, and a host of mediators that are produced during sepsis may induce EC apoptosis. These include TNF-alpha, interleukin (IL)-1, interferon, oxygen-containing free radicals, and hypoxia. In addition, LPS-activated monocytes promote programmed cell death in ECs by a combination of TNF-alpha-dependent and -independent mechanisms [75].

EC apoptosis results in an accentuated proinflammatory response. Under in vitro conditions, apoptotic ECs mediate IL-1-dependent paracrine induction of ICAM-1 and VCAM-1, increased production of reactive oxygen species, increased procoagulant activity, decreased production of prostacyclin, and complement activation. ECs undergoing apoptosis also demonstrate increased binding to nonactivated platelets [76].

In a mouse model of endotoxemia, intraperitoneally delivered LPS resulted in widespread apoptosis of the endothelium, while in other studies, the intravenous administration of LPS induced EC apoptosis in the lung, but not the liver, again demonstrating organ-specific differences in endothelial response.

Local versus systemic endothelial activation — The innate host response evolved as a local mechanism to eradicate pathogens and necrotic tissue. The endothelium orchestrates this response by promoting the adhesion and transmigration of leukocytes, inducing thrombin generation and fibrin formation, altering local vasomotor tone, increasing vascular permeability, and triggering programmed cell death [77]. Normally, this is a compartmentalized process.

However, when the host endothelial response becomes generalized, a dysregulated, inflammatory response ensues. Such widespread endothelial involvement may lead to the systemic inflammatory response syndrome (SIRS) and/or the multiple organ dysfunction syndrome (MODS). (See "Sepsis syndromes in adults: Epidemiology, definitions, clinical presentation, diagnosis, and prognosis".) Endothelial cell dysfunction in sepsis arises from an otherwise adaptive response. Therefore, targeting the host response too early may worsen patient outcome. Indeed, it is tempting to speculate that some of the failures in sepsis trials may be related to inadvertent interference with adaptive mechanisms.

Immunomodulation — Single cell analyses have revealed a much greater role for ECs in innate immunity than was previously thought. Transcriptional profiling studies suggest that ECs can demonstrate phagocytic activity, antigen presentation capability, and cytokine production for immune cell recruitment [78]. (See "Antigen-presenting cells" and "An overview of the innate immune system".)

These properties appear to vary by the type of tissue and type of blood vessel. ECs may therefore serve as new therapeutic targets for immunomodulation.

COMPLEMENT-MEDIATED ENDOTHELIAL CELL INJURY — Endothelial cells express a range of complement receptors and complement regulatory proteins, and are subject to attack by complement [79]. The C5b-9 membrane attack complex (MAC) can induce endothelial cell lysis, while sub-lytic amounts of MAC may activate the cells to release proinflammatory P-selectin and procoagulant von Willebrand factor, and may also disturb normal endothelial cell barrier function [80]. Examples of the clinical use of anti-complement therapies in endothelial disorders include the following:

Complement-mediated thrombotic microangiopathy (TMA), also called complement-mediated hemolytic uremic syndrome (HUS), is associated with mutations or autoantibodies that lead to excessive complement activation. Renal endothelial cells appear to be especially sensitive to complement-mediated injury, thus providing a possible rationale for the efficacy of complement inhibition in this setting. The treatment of complement-mediated TMA with anti-complement therapy is discussed in detail separately. (See "Complement-mediated hemolytic uremic syndrome in children", section on 'Treatment'.)

In antibody-mediated transplant rejection, antibodies directed against endothelial cell antigens, most often HLA-A, B, C and DR, may kill or disable endothelial cells by excessive activation of complement.

In age-related macular degeneration, a major cause of blindness, polymorphisms in the allele for complement factor H (CFH) account for approximately 43 to 50 percent of the disease in older adults; it is hypothesized that these changes impair the ability of CFH to suppress complement activation and hence endothelial cell damage. (See "Age-related macular degeneration", section on 'Pathogenesis'.)

EVALUATION OF ENDOTHELIAL DISORDERS — One approach to studying endothelial cell (EC) function in vivo involves the use of strategically placed catheters that allow the examiner to sample blood from a specific vascular bed. Thus, coronary endothelial function can be evaluated in humans by selective infusion of acetylcholine into the epicardial coronary arteries, followed by measurement of vessel diameter and Doppler-derived velocity to calculate coronary blood flow. Using this technique, studies have revealed that coronary endothelial dysfunction is common in patients with coronary artery disease [27].

In addition, newer proteomics techniques are likely to provide novel platforms (eg, protein-based chips) that will allow the practitioner to simultaneously monitor a panel of endothelial cell function biomarkers. For example, proteomics may be valuable in determining the presence or absence of specific complications (eg, graft versus host disease or sepsis) in patients undergoing hematopoietic cell transplantation [81], in understanding changes in blood-brain barrier function in central nervous system disease [82,83], or in assessing the pathologic mechanisms in stroke [84]. By extension, a more comprehensive and systematic analysis of pathological specimens (eg, skin biopsies) might provide even more robust data that reflect EC function.

Imaging studies, such as Doppler measurements of blood flow, magnetic resonance angiography and computed tomography (CT) scanning are widely available in clinical practice and should be applicable to the study of EC (dys)function. Molecular imaging, which combines the power of proteomics with advanced labeling techniques, could revolutionize the diagnosis of endothelial-based disorders [85,86].

Circulating endothelial cells — Refined protocols to isolate and interrogate the phenotype of circulating endothelial cells (CEC) and their progenitors may yield insight into their function or their bed-of-origin [87-95]. Thus, measurement of a panel of activation markers, rather than a single mediator, may yield previously unappreciated response patterns that will aid in diagnosis, monitoring, and/or treatment of vascular and coagulation disorders [90,96,97].

Microparticles — Microparticles may possibly serve as a means of intercellular communication in hemostasis and vascular biology [98]. Microparticles are vesicles of submicron size that are shed from plasma membranes in response to cell activation, injury, or apoptosis [99]. Although still in the development stage, enumeration of microparticles before and during treatment may prove helpful in revealing the degree of endothelial damage, as well as their response to treatment in various disorders involving microvascular injury [100-106]. (See "Cancer-associated hypercoagulable state: Causes and mechanisms", section on 'Biomarkers'.)

Peripheral venous endothelial cell biopsy — Protocols are available for obtaining endothelial cells from peripheral veins; these cells can be plated on poly-L-lysine coated microscope slides, treated in the absence or presence of agonists, and assayed for protein or mRNA expression. This approach has been used to provide evidence for the presence of altered eNOS activation, reduced insulin action, and inflammatory activation in the endothelium of patients with diabetes mellitus [107].

Blood outgrowth endothelial cells — Blood outgrowth endothelial cells (BOECs; also called late outgrowth endothelial progenitor cells or endothelial colony-forming cells) are bone marrow-derived stem cells that have the ability to differentiate into mature ECs [108]. They can be cryopreserved, subjected to gene transfer, and further expanded for vascular repair. They have been implicated in postnatal vasculogenesis and endothelial repair at sites of endothelial damage. These cells have been isolated from patients with several endothelial-based diseases, including von Willebrand disease and sickle cell disease, where they have provided important new insights into underlying pathophysiology and diagnosis [109-112].

TREATMENT OF ENDOTHELIAL DISORDERS — The endothelium is an attractive therapeutic target:

It is strategically located between the circulating blood and every tissue, and is therefore rapidly and preferentially exposed to systemically administered agents.

As a result of its high degree of plasticity, it should be amenable to therapeutic manipulation.

Due to its close proximity to underlying tissues, the endothelium provides a direct line of communication to all organs of the body.

Some examples of endothelial cell (EC)-targeted therapies are outlined below.

Severe sepsis — Endothelial function is altered in sepsis, and enormous resources have been expended on sepsis trials, with more than 10,000 patients enrolled in over 20 randomized trials. In patients with severe sepsis, most therapies, including anti-endotoxin, anti-cytokine, anti-prostaglandin, anti-bradykinin, anti-platelet activating factor strategies, antithrombin, activated protein C, and tissue factor pathway inhibitor have failed to reduce mortality; no specific antisepsis treatments are available [113]. A discussion of sepsis management is presented in detail separately. (See "Management and outcome of sepsis in term and late preterm neonates" and "Evaluation and management of suspected sepsis and septic shock in adults".)

Sickle cell disease — Nitric oxide (NO) metabolism is abnormal in patients with sickle cell disease, both at baseline and during acute illnesses, and may contribute to such complications as the acute chest syndrome (ACS), pulmonary hypertension, and priapism. This may be the result of increased plasma levels of cell-free hemoglobin secondary to hemolysis, which depletes NO. (See "Pulmonary hypertension associated with sickle cell disease", section on 'Pathogenesis' and "Priapism and erectile dysfunction in sickle cell disease", section on 'Mechanisms of priapism'.)

Inhaled NO was investigated as a therapy for ACS but found to be ineffective. (See "Acute chest syndrome (ACS) in sickle cell disease (adults and children)", section on 'Inhaled nitric oxide'.)

Idiopathic pulmonary arterial hypertension — Endothelin-receptor antagonists may be effective in treating some forms of pulmonary artery hypertension. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy".) In the neonate, NO has been used to treat pulmonary hypertension, which may be either idiopathic or part of a cardiovascular or infectious disorder. NO has also been effective in treating hypoxic respiratory failure in term or near-term infants [114]. NO is the only US Food and Drug Administration (FDA)-approved pulmonary vasodilator that can be used during mechanical ventilation [115].

Macular degeneration — Antiangiogenic approaches directed at inhibiting the action of vascular endothelial growth factor (VEGF) may have a significant impact on the progression of age-related macular degeneration.

Diabetic retinopathy — Anti-VEGF modalities are standard-of-care options for proliferative diabetic retinopathy and diabetic macular edema [116-118]. (See "Diabetic retinopathy: Pathogenesis" and "Diabetic retinopathy: Prevention and treatment".)

Retinopathy of prematurity — In premature infants, anti-VEGF is also used to treat retinopathy of prematurity, but further studies are needed to assess potential long-term effects on neurocognitive development and myocardial health [119]. (See "Retinopathy of prematurity (ROP): Risk factors, classification, and screening" and "Retinopathy of prematurity (ROP): Treatment and prognosis".)

SUMMARY

Where are they? – Endothelial cells (ECs) form the lining of all blood and lymphatic vessels within the vascular tree. The adult human body contains at least one trillion endothelial cells, which cover a surface area of >3000 square meters. (See 'Introduction' above.)

What do they do? – The endothelium mediates vasomotor tone, regulates cellular and nutrient trafficking, maintains blood fluidity, contributes to the local balance between pro- and anti-inflammatory mediators as well as procoagulant and anticoagulant activity, participates in generation of new blood vessels, interacts with circulating blood cells, and undergoes programmed cell death. Each of these activities is dynamically regulated in both space and time. (See 'Endothelial heterogeneity' above.)

How are they regulated? – Because endothelial cells receive cues from a wide variety of cells and tissues, they possess disparate properties that are specific to their local environment. This "heterogeneity" is a central feature of the endothelium, and includes variations in morphology, biosynthetic repertoire, and behavior. (See 'Patterns of change in endothelial function' above.)

Evaluation – Endothelial cell disorders can be evaluated in several ways. Placement of catheters within specific vascular beds may allow for proteomic analysis of endothelial cell metabolites or biomarkers. Vasculature can be imaged, and flow can be measured, by Doppler, magnetic resonance angiography, and computed tomography (CT) scanning. Circulating endothelial cells or their shed microparticles can be harvested by direct biopsy or by collecting circulating progenitor cells that can be expanded and studied further in vitro. (See 'Evaluation of endothelial disorders' above.)

Clinical relevance – Some conditions in which endothelial function is disturbed and for which treatments are discussed above, include COVID-19, sepsis, disseminated intravascular coagulation (DIC), acute chest syndrome in sickle cell disease, pulmonary hypertension, and macular degeneration. Gene expression atlases derived from single cell profiling studies may be used to identify functional differences in endothelial cells that could serve as new therapeutic targets. (See 'Sepsis as a model endotheliopathy' above and 'Treatment of endothelial disorders' above.)

  1. Jaffe EA. Cell biology of endothelial cells. Hum Pathol 1987; 18:234.
  2. Cliff WJ. Blood Vessels, Cambridge University Press, New York 1976.
  3. Gross PL, Aird WC. The endothelium and thrombosis. Semin Thromb Hemost 2000; 26:463.
  4. Wagner DD, Frenette PS. The vessel wall and its interactions. Blood 2008; 111:5271.
  5. Yano K, Gale D, Massberg S, et al. Phenotypic heterogeneity is an evolutionarily conserved feature of the endothelium. Blood 2007; 109:613.
  6. Aird WC. Spatial and temporal dynamics of the endothelium. J Thromb Haemost 2005; 3:1392.
  7. Nachman RL, Jaffe EA. Endothelial cell culture: beginnings of modern vascular biology. J Clin Invest 2004; 114:1037.
  8. Trimm E, Red-Horse K. Vascular endothelial cell development and diversity. Nat Rev Cardiol 2023; 20:197.
  9. Aird WC. Endothelial cell heterogeneity. Cold Spring Harb Perspect Med 2012; 2:a006429.
  10. Hajjar KA. Vascular biology. In: Clinical Hematology, Young NS, Gerson SL, High KA (Eds), Mosby Elsevier, Philadelphia 2006. p.125.
  11. Cines DB, Pollak ES, Buck CA, et al. Endothelial cells in physiology and in the pathophysiology of vascular disorders. Blood 1998; 91:3527.
  12. Aird WC. Endothelial cell heterogeneity. Crit Care Med 2003; 31:S221.
  13. Stevens T, Rosenberg R, Aird W, et al. NHLBI workshop report: endothelial cell phenotypes in heart, lung, and blood diseases. Am J Physiol Cell Physiol 2001; 281:C1422.
  14. Aird WC. Vascular bed-specific hemostasis: role of endothelium in sepsis pathogenesis. Crit Care Med 2001; 29:S28.
  15. Oh P, Li Y, Yu J, et al. Subtractive proteomic mapping of the endothelial surface in lung and solid tumours for tissue-specific therapy. Nature 2004; 429:629.
  16. Pasqualini R, Ruoslahti E. Organ targeting in vivo using phage display peptide libraries. Nature 1996; 380:364.
  17. Amatschek S, Kriehuber E, Bauer W, et al. Blood and lymphatic endothelial cell-specific differentiation programs are stringently controlled by the tissue environment. Blood 2007; 109:4777.
  18. Griffin NM, Schnitzer JE. Chapter 8. Proteomic mapping of the vascular endothelium in vivo for vascular targeting. Methods Enzymol 2008; 445:177.
  19. Brooks EG, Trotman W, Wadsworth MP, et al. Valves of the deep venous system: an overlooked risk factor. Blood 2009; 114:1276.
  20. Solovey A, Kollander R, Shet A, et al. Endothelial cell expression of tissue factor in sickle mice is augmented by hypoxia/reoxygenation and inhibited by lovastatin. Blood 2004; 104:840.
  21. Weninger W, Ulfman LH, Cheng G, et al. Specialized contributions by alpha(1,3)-fucosyltransferase-IV and FucT-VII during leukocyte rolling in dermal microvessels. Immunity 2000; 12:665.
  22. Dekker RJ, van Soest S, Fontijn RD, et al. Prolonged fluid shear stress induces a distinct set of endothelial cell genes, most specifically lung Krüppel-like factor (KLF2). Blood 2002; 100:1689.
  23. Ungvari Z, Tarantini S, Kiss T, et al. Endothelial dysfunction and angiogenesis impairment in the ageing vasculature. Nat Rev Cardiol 2018; 15:555.
  24. Florey . The endothelial cell. Br Med J 1966; 2:487.
  25. Ross R, Glomset JA. Atherosclerosis and the arterial smooth muscle cell: Proliferation of smooth muscle is a key event in the genesis of the lesions of atherosclerosis. Science 1973; 180:1332.
  26. Endothelial Dysfunction and the Pathogenesis of Atherosclerosis, Gimbrone MA Jr (Ed), Springer-Verlag, New York 1980.
  27. Ludmer PL, Selwyn AP, Shook TL, et al. Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries. N Engl J Med 1986; 315:1046.
  28. Cybulsky MI, Gimbrone MA Jr. Endothelial expression of a mononuclear leukocyte adhesion molecule during atherogenesis. Science 1991; 251:788.
  29. Osborn L, Hession C, Tizard R, et al. Direct expression cloning of vascular cell adhesion molecule 1, a cytokine-induced endothelial protein that binds to lymphocytes. Cell 1989; 59:1203.
  30. Hasstedt SJ, Bezemer ID, Callas PW, et al. Cell adhesion molecule 1: a novel risk factor for venous thrombosis. Blood 2009; 114:3084.
  31. Hajjar KA, Muller WA. Chapter 114: Vascular function in hemostasis. In Williams Hematology, 10th ed, Kaushansky K, Prchal JT, Burns LJ, Lichtman MA, Levi M, Linch DC (Eds), McGraw Hill, 2021. p.2067.
  32. Fassel H, Chen H, Ruisi M, et al. Reduced expression of annexin A2 is associated with impaired cell surface fibrinolysis and venous thromboembolism. Blood 2021; 137:2221.
  33. Matthay MA, Aldrich JM, Gotts JE. Treatment for severe acute respiratory distress syndrome from COVID-19. Lancet Respir Med 2020; 8:433.
  34. Berlin DA, Gulick RM, Martinez FJ. Severe Covid-19. N Engl J Med 2020; 383:2451.
  35. Fauci AS, Lane HC, Redfield RR. Covid-19 - Navigating the Uncharted. N Engl J Med 2020; 382:1268.
  36. Wadman M, Couzin-Frankel J, Kaiser J, Matacic C. A rampage through the body. Science 2020; 368:356.
  37. Varga Z, Flammer AJ, Steiger P, et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet 2020; 395:1417.
  38. Ackermann M, Verleden SE, Kuehnel M, et al. Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19. N Engl J Med 2020; 383:120.
  39. Magro C, Mulvey JJ, Berlin D, et al. Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: A report of five cases. Transl Res 2020; 220:1.
  40. Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016; 315:801.
  41. Aird WC. The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome. Blood 2003; 101:3765.
  42. Lemichez E, Lecuit M, Nassif X, Bourdoulous S. Breaking the wall: targeting of the endothelium by pathogenic bacteria. Nat Rev Microbiol 2010; 8:93.
  43. Lee WL, Slutsky AS. Sepsis and endothelial permeability. N Engl J Med 2010; 363:689.
  44. Volk T, Kox WJ. Endothelium function in sepsis. Inflamm Res 2000; 49:185.
  45. Faure E, Thomas L, Xu H, et al. Bacterial lipopolysaccharide and IFN-gamma induce Toll-like receptor 2 and Toll-like receptor 4 expression in human endothelial cells: role of NF-kappa B activation. J Immunol 2001; 166:2018.
  46. Henneke P, Golenbock DT. Innate immune recognition of lipopolysaccharide by endothelial cells. Crit Care Med 2002; 30:S207.
  47. Zhang FX, Kirschning CJ, Mancinelli R, et al. Bacterial lipopolysaccharide activates nuclear factor-kappaB through interleukin-1 signaling mediators in cultured human dermal endothelial cells and mononuclear phagocytes. J Biol Chem 1999; 274:7611.
  48. Zhao B, Bowden RA, Stavchansky SA, Bowman PD. Human endothelial cell response to gram-negative lipopolysaccharide assessed with cDNA microarrays. Am J Physiol Cell Physiol 2001; 281:C1587.
  49. Brown KA, Brain SD, Pearson JD, et al. Neutrophils in development of multiple organ failure in sepsis. Lancet 2006; 368:157.
  50. Vallet B, Wiel E. Endothelial cell dysfunction and coagulation. Crit Care Med 2001; 29:S36.
  51. Lacroix R, Sabatier F, Mialhe A, et al. Activation of plasminogen into plasmin at the surface of endothelial microparticles: a mechanism that modulates angiogenic properties of endothelial progenitor cells in vitro. Blood 2007; 110:2432.
  52. Drake TA, Cheng J, Chang A, Taylor FB Jr. Expression of tissue factor, thrombomodulin, and E-selectin in baboons with lethal Escherichia coli sepsis. Am J Pathol 1993; 142:1458.
  53. Lupu C, Westmuckett AD, Peer G, et al. Tissue factor-dependent coagulation is preferentially up-regulated within arterial branching areas in a baboon model of Escherichia coli sepsis. Am J Pathol 2005; 167:1161.
  54. Faust SN, Levin M, Harrison OB, et al. Dysfunction of endothelial protein C activation in severe meningococcal sepsis. N Engl J Med 2001; 345:408.
  55. Ishii H, Salem HH, Bell CE, et al. Thrombomodulin, an endothelial anticoagulant protein, is absent from the human brain. Blood 1986; 67:362.
  56. Bombeli T, Karsan A, Tait JF, Harlan JM. Apoptotic vascular endothelial cells become procoagulant. Blood 1997; 89:2429.
  57. Nachman RL, Rafii S. Platelets, petechiae, and preservation of the vascular wall. N Engl J Med 2008; 359:1261.
  58. Chen D, Giannopoulos K, Shiels PG, et al. Inhibition of intravascular thrombosis in murine endotoxemia by targeted expression of hirudin and tissue factor pathway inhibitor analogs to activated endothelium. Blood 2004; 104:1344.
  59. Aird WC, Mosnier LO, Fairhurst RM. Plasmodium falciparum picks (on) EPCR. Blood 2014; 123:163.
  60. Weiler H, Lindner V, Kerlin B, et al. Characterization of a mouse model for thrombomodulin deficiency. Arterioscler Thromb Vasc Biol 2001; 21:1531.
  61. Yanada M, Kojima T, Ishiguro K, et al. Impact of antithrombin deficiency in thrombogenesis: lipopolysaccharide and stress-induced thrombus formation in heterozygous antithrombin-deficient mice. Blood 2002; 99:2455.
  62. André P. P-selectin in haemostasis. Br J Haematol 2004; 126:298.
  63. Miyasaka M, Tanaka T. Lymphocyte trafficking across high endothelial venules: dogmas and enigmas. Nat Rev Immunol 2004; 4:360.
  64. Ley K. Integration of inflammatory signals by rolling neutrophils. Immunol Rev 2002; 186:8.
  65. Wright CE, Rees DD, Moncada S. Protective and pathological roles of nitric oxide in endotoxin shock. Cardiovasc Res 1992; 26:48.
  66. Feihl F, Waeber B, Liaudet L. Is nitric oxide overproduction the target of choice for the management of septic shock? Pharmacol Ther 2001; 91:179.
  67. Crawford JH, Chacko BK, Pruitt HM, et al. Transduction of NO-bioactivity by the red blood cell in sepsis: novel mechanisms of vasodilation during acute inflammatory disease. Blood 2004; 104:1375.
  68. Lee WL, Slutsky AS. Sepsis and endothelial permeability. N Engl J Med 2010; 363:689.
  69. Yano K, Liaw PC, Mullington JM, et al. Vascular endothelial growth factor is an important determinant of sepsis morbidity and mortality. J Exp Med 2006; 203:1447.
  70. Parikh SM. Dysregulation of the angiopoietin-Tie-2 axis in sepsis and ARDS. Virulence 2013; 4:517.
  71. Parikh SM. Angiopoietins and Tie2 in vascular inflammation. Curr Opin Hematol 2017; 24:432.
  72. Ushiyama A, Kataoka H, Iijima T. Glycocalyx and its involvement in clinical pathophysiologies. J Intensive Care 2016; 4:59.
  73. Martin L, Koczera P, Zechendorf E, Schuerholz T. The Endothelial Glycocalyx: New Diagnostic and Therapeutic Approaches in Sepsis. Biomed Res Int 2016; 2016:3758278.
  74. Luo M, Flood EC, Almeida D, et al. Annexin A2 supports pulmonary microvascular integrity by linking vascular endothelial cadherin and protein tyrosine phosphatases. J Exp Med 2017; 214:2535.
  75. Lindner H, Holler E, Ertl B, et al. Peripheral blood mononuclear cells induce programmed cell death in human endothelial cells and may prevent repair: role of cytokines. Blood 1997; 89:1931.
  76. Bombeli T, Schwartz BR, Harlan JM. Endothelial cells undergoing apoptosis become proadhesive for nonactivated platelets. Blood 1999; 93:3831.
  77. McCuskey RS, Urbaschek R, Urbaschek B. The microcirculation during endotoxemia. Cardiovasc Res 1996; 32:752.
  78. Amersfoort J, Eelen G, Carmeliet P. Immunomodulation by endothelial cells - partnering up with the immune system? Nat Rev Immunol 2022; 22:576.
  79. Brooimans RA, van Wieringen PA, van Es LA, Daha MR. Relative roles of decay-accelerating factor, membrane cofactor protein, and CD59 in the protection of human endothelial cells against complement-mediated lysis. Eur J Immunol 1992; 22:3135.
  80. Kerr H, Richards A. Complement-mediated injury and protection of endothelium: lessons from atypical haemolytic uraemic syndrome. Immunobiology 2012; 217:195.
  81. Kaiser T, Kamal H, Rank A, et al. Proteomics applied to the clinical follow-up of patients after allogeneic hematopoietic stem cell transplantation. Blood 2004; 104:340.
  82. Pottiez G, Flahaut C, Cecchelli R, Karamanos Y. Understanding the blood-brain barrier using gene and protein expression profiling technologies. Brain Res Rev 2009; 62:83.
  83. Karamanos Y, Pottiez G. Proteomics and the blood-brain barrier: how recent findings help drug development. Expert Rev Proteomics 2016; 13:251.
  84. Baird AE, Wright VL. Vascular biology: cellular and molecular profiling. Semin Neurol 2006; 26:65.
  85. Mori N, Natarajan K, Chacko VP, et al. Choline phospholipid metabolites of human vascular endothelial cells altered by cyclooxygenase inhibition, growth factor depletion, and paracrine factors secreted by cancer cells. Mol Imaging 2003; 2:124.
  86. Padera TP, Stoll BR, So PT, Jain RK. Conventional and high-speed intravital multiphoton laser scanning microscopy of microvasculature, lymphatics, and leukocyte-endothelial interactions. Mol Imaging 2002; 1:9.
  87. Blann AD, Woywodt A, Bertolini F, et al. Circulating endothelial cells. Biomarker of vascular disease. Thromb Haemost 2005; 93:228.
  88. Chirinos JA, Heresi GA, Velasquez H, et al. Elevation of endothelial microparticles, platelets, and leukocyte activation in patients with venous thromboembolism. J Am Coll Cardiol 2005; 45:1467.
  89. Yoder MC, Mead LE, Prater D, et al. Redefining endothelial progenitor cells via clonal analysis and hematopoietic stem/progenitor cell principals. Blood 2007; 109:1801.
  90. Lynch SF, Ludlam CA. Plasma microparticles and vascular disorders. Br J Haematol 2007; 137:36.
  91. Deregibus MC, Cantaluppi V, Calogero R, et al. Endothelial progenitor cell derived microvesicles activate an angiogenic program in endothelial cells by a horizontal transfer of mRNA. Blood 2007; 110:2440.
  92. Ghosh A, Li W, Febbraio M, et al. Platelet CD36 mediates interactions with endothelial cell-derived microparticles and contributes to thrombosis in mice. J Clin Invest 2008; 118:1934.
  93. Shantsila E, Blann AD, Lip GY. Circulating endothelial cells: from bench to clinical practice. J Thromb Haemost 2008; 6:865.
  94. Mancuso P, Antoniotti P, Quarna J, et al. Validation of a standardized method for enumerating circulating endothelial cells and progenitors: flow cytometry and molecular and ultrastructural analyses. Clin Cancer Res 2009; 15:267.
  95. Tilki D, Hohn HP, Ergün B, et al. Emerging biology of vascular wall progenitor cells in health and disease. Trends Mol Med 2009; 15:501.
  96. Körbling M, Reuben JM, Gao H, et al. Recombinant human granulocyte-colony-stimulating factor-mobilized and apheresis-collected endothelial progenitor cells: a novel blood cell component for therapeutic vasculogenesis. Transfusion 2006; 46:1795.
  97. Bidot L, Jy W, Bidot C Jr, et al. Microparticle-mediated thrombin generation assay: increased activity in patients with recurrent thrombosis. J Thromb Haemost 2008; 6:913.
  98. Ridger VC, Boulanger CM, Angelillo-Scherrer A, et al. Microvesicles in vascular homeostasis and diseases. Position Paper of the European Society of Cardiology (ESC) Working Group on Atherosclerosis and Vascular Biology. Thromb Haemost 2017; 117:1296.
  99. Chironi GN, Boulanger CM, Simon A, et al. Endothelial microparticles in diseases. Cell Tissue Res 2009; 335:143.
  100. Erdbruegger U, Woywodt A, Kirsch T, et al. Circulating endothelial cells as a prognostic marker in thrombotic microangiopathy. Am J Kidney Dis 2006; 48:564.
  101. Woywodt A, Goldberg C, Kirsch T, et al. Circulating endothelial cells in relapse and limited granulomatous disease due to ANCA associated vasculitis. Ann Rheum Dis 2006; 65:164.
  102. Solovey A, Lin Y, Browne P, et al. Circulating activated endothelial cells in sickle cell anemia. N Engl J Med 1997; 337:1584.
  103. Mutin M, Canavy I, Blann A, et al. Direct evidence of endothelial injury in acute myocardial infarction and unstable angina by demonstration of circulating endothelial cells. Blood 1999; 93:2951.
  104. Widemann A, Sabatier F, Arnaud L, et al. CD146-based immunomagnetic enrichment followed by multiparameter flow cytometry: a new approach to counting circulating endothelial cells. J Thromb Haemost 2008; 6:869.
  105. Jourde-Chiche N, Dou L, Sabatier F, et al. Levels of circulating endothelial progenitor cells are related to uremic toxins and vascular injury in hemodialysis patients. J Thromb Haemost 2009; 7:1576.
  106. Georgescu A, Alexandru N, Popov D, et al. Chronic venous insufficiency is associated with elevated level of circulating microparticles. J Thromb Haemost 2009; 7:1566.
  107. Tabit CE, Shenouda SM, Holbrook M, et al. Protein kinase C-β contributes to impaired endothelial insulin signaling in humans with diabetes mellitus. Circulation 2013; 127:86.
  108. Hebbel RP. Blood endothelial cells: utility from ambiguity. J Clin Invest 2017; 127:1613.
  109. Starke RD, Paschalaki KE, Dyer CE, et al. Cellular and molecular basis of von Willebrand disease: studies on blood outgrowth endothelial cells. Blood 2013; 121:2773.
  110. Wang JW, Bouwens EA, Pintao MC, et al. Analysis of the storage and secretion of von Willebrand factor in blood outgrowth endothelial cells derived from patients with von Willebrand disease. Blood 2013; 121:2762.
  111. Enenstein J, Milbauer L, Domingo E, et al. Proinflammatory phenotype with imbalance of KLF2 and RelA: risk of childhood stroke with sickle cell anemia. Am J Hematol 2010; 85:18.
  112. Paschalaki KE, Randi AM. Recent Advances in Endothelial Colony Forming Cells Toward Their Use in Clinical Translation. Front Med (Lausanne) 2018; 5:295.
  113. Cohen J, Vincent JL, Adhikari NK, et al. Sepsis: a roadmap for future research. Lancet Infect Dis 2015; 15:581.
  114. Barrington KJ, Finer N, Pennaforte T, Altit G. Nitric oxide for respiratory failure in infants born at or near term. Cochrane Database Syst Rev 2017; 1:CD000399.
  115. Davis MD, Donn SM, Ward RM. Administration of Inhaled Pulmonary Vasodilators to the Mechanically Ventilated Neonatal Patient. Paediatr Drugs 2017; 19:183.
  116. Stewart MW. Treatment of diabetic retinopathy: Recent advances and unresolved challenges. World J Diabetes 2016; 7:333.
  117. Ajlan RS, Silva PS, Sun JK. Vascular Endothelial Growth Factor and Diabetic Retinal Disease. Semin Ophthalmol 2016; 31:40.
  118. Dhoot DS, Avery RL. Vascular Endothelial Growth Factor Inhibitors for Diabetic Retinopathy. Curr Diab Rep 2016; 16:122.
  119. Sankar MJ, Sankar J, Mehta M, et al. Anti-vascular endothelial growth factor (VEGF) drugs for treatment of retinopathy of prematurity. Cochrane Database Syst Rev 2016; 2:CD009734.
Topic 1330 Version 36.0

References

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