221CHAPTER 25 Endothelium and Endotheliopathy Therefore, NO contributes to the balance between vasodilator and vasoconstrictor influences that determine vascular tone 31 Prostacyclin Another major end[.]
CHAPTER 25 Endothelium and Endotheliopathy 221 Therefore, NO contributes to the balance between vasodilator and vasoconstrictor influences that determine vascular tone.31 Endothelium-Derived Vasoconstrictors Prostacyclin Another major endothelium-derived vasodilator is the prostaglandin prostacyclin (PGI2), a derivative of arachidonic acid synthesized through the action of the enzyme cyclooxygenase Endothelium cells are capable of producing a variety of vasoactive substances that are products of arachidonic acid metabolism Among these are prostaglandins, PGI2, leukotrienes, and thromboxanes These substances act as either vasodilators or vasoconstrictors, among their other biological activities PGI2 is a potent vasodilator and is active in both the pulmonary and systemic circulations In addition to its vasodilatory effects, prostacyclin also has antithrombotic and antiplatelet activity Its release may be stimulated by bradykinin and adenine nucleotides Like NO, it is chemically unstable, with a short half-life.32 However, unlike NO, PGI2 activity in arterial beds depends on its ability to bind to specific receptors in vascular smooth muscle Therefore, its vasodilator activity is determined by the expression of such receptors PGI2 receptors are coupled to adenylate cyclase to elevate cyclic adenosine monophosphate (cAMP) levels in vascular smooth muscle.33 The increase in cAMP results in (1) stimulation of adenosine triphosphate (ATP)-sensitive K1 channels, leading to hyperpolarization of the cell membrane and inhibition of the development of contraction; and (2) increased efflux of calcium ions (Ca21) from the smooth muscle cell and inhibition of the contractile machinery In addition, PGI2 facilitates the release of NO by endothelial cells, and NO potentiates the action of PGI2 in vascular smooth muscle Interestingly, NO may also potentiate the effects of prostacyclin The NO-mediated increase in cGMP in smooth muscle cells inhibits a phosphodiesterase that breaks down cAMP and therefore indirectly prolongs the half-life of the second messenger of PGI2.34 Endothelin is a 21-amino-acid peptide and is one of the most potent vasoconstrictors identified to date Endothelial cells synthesize the prohormone big endothelin and express endothelinconverting enzymes to generate endothelin There are three isoforms of endothelin, but only one (ET-1) has been shown to be released from human endothelial cells ET-1 is synthesized in the endothelial cells Its release is mediated by a variety of stimuli ET-1 release is stimulated by angiotensin II, antidiuretic hormone, thrombin, cytokines, reactive oxygen species, and shearing forces acting on the vascular endothelium ET-1 release is inhibited by NO as well as by PGI2 and atrial natriuretic peptide.36,37 ET-1 has a short half-life, suggesting that, similarly to NO, ET-1 is mainly a locally active vasoregulator Once released by endothelial cells, ET-1 binds to a membrane receptor (ETA) found on adjacent vascular smooth muscle cells This binding leads to calcium mobilization and smooth muscle contraction The ETA receptor is coupled with a G-protein linked to phospholipase-C, resulting in the formation of IP3 Interestingly, ET-1 can also bind to an ETB receptor located on the vascular endothelium, which stimulates the formation of NO by the endothelium This release of NO appears to modulate the ETA receptor–mediated contraction of the vascular smooth muscle Its physiologic role includes maintenance of basal vascular resistance, and it is present in healthy subjects in low concentrations Endothelium-Derived Hyperpolarizing Factor Endothelium stimulation by acetylcholine also produces hyperpolarization of the underlying smooth muscle and thereby induces vasorelaxation This process is not mediated by NO but is instead mediated by another endothelium-derived factor This factor increases K1-channel conductance in smooth muscle cells, resulting in smooth muscle cell relaxation The resulting vasodilation is not inhibited by NG-methyl-L-arginine (L-NMMA), the specific antagonist of NO, but rather is inhibited by ouabain, a sodiumpotassium adenosine triphosphatase inhibitor In addition, in most medium- to resistance-sized arteries, electrophysiologic studies have established that endothelium-dependent hyperpolarization of vascular smooth muscle is resistant to the combined inhibition of both NOs and cyclooxygenases Accordingly, a component of the endothelium-dependent relaxation in these arteries is mediated by a substance different from NO and PGI2 This component of endothelium-dependent vasodilation has been attributed to an as yet unidentified diffusible endotheliumderived hyperpolarizing factor (EDHF).35 Of significant clinical importance is the fact that the EDHFmediated effect increases as the arterial diameter decreases, such as in resistance arteries EDHF likely plays a significant role in the regulation of peripheral vascular resistance and local hemodynamics Unfortunately, in the absence of selective inhibitors of the EDHF pathway, it is not possible to evaluate the relevance of EDHF in vivo.35 Endothelins (Endothelium-Derived Contracting Factors) Reactive Oxygen Species Endothelial cells secrete oxygen-derived free radicals and hydrogen peroxide in response to shear stress and endothelial agonists such as bradykinin Such reactive oxygen species are reported to inactivate NO, resulting in vasoconstriction Reactive oxygen species may also facilitate the mobilization of cytosolic Ca21 in vascular smooth muscle cells and promote Ca21 sensitization of the contractile elements Under conditions of hyperoxia, endotheliumderived superoxide anion may combine with NO with diffusionlimited kinetics to generate peroxynitrite, negating NO-mediated vasodilation, an effect inhibited by superoxide dismutase, which metabolizes superoxide anion to hydrogen peroxide.38 Vasoconstrictor Prostaglandins The metabolism of arachidonic acid by cyclooxygenase in endothelial cells may lead to the secretion of precursors of thromboxanes and leukotrienes These prostaglandins act on receptors in vascular smooth muscle to induce vasoconstriction PGI2, however, is the major endothelial metabolite of arachidonic acid that is generated through the cyclooxygenase pathway Thus, under normal circumstances, the influence of the small amounts of vasoconstrictor prostanoids released by endothelial cells is masked by the production of PGI2, NO, and EDHF.39,40 Endothelium and Blood Cell Interactions In addition to the interactions of the endothelium with blood coagulation factors, endothelial cells also express cell-surface molecules known as the endothelial glycocalyx (EG) Over the past decade, we have learned about the role of the glycocalyx in vascular physiology and pathology, including mechanotransduction, hemostasis, signaling, and blood cell–vessel wall interactions The glycocalyx is a gel-like layer enriched with carbohydrates Its dimensions vary according to the type of vasculature, ranging from 222 S E C T I O N I V Pediatric Critical Care: Cardiovascular Neutrophils Intact glycocalyx Integrin Lack of permeability Transmigration Rolling and Firm Tethering integrin adhesion activation Selectin receptor Lack of leukocyte attachment Glycocalyx E-selectin Selectin expression Endothelial cell ICAM Inflammatory stimulus Injured glycocalyx Extracellular matrix • Fig 25.5 Leukocyte recruitment process and transmigration The multiIncreased permeability Leukocyte translocation • Fig 25.4 Physiologic role of the intact glycocalyx The endothelial glyco- calyx is an important determinant of vascular permeability, influences blood cell–vessel wall interactions, acts as a mechanotransducer, and binds to plasma proteins The injured glycocalyx leads to impaired mechanotransduction, increased leukocyte egress, loss of coagulation control, and increased permeability 0.2 mm to more than mm The EG consists of various types of glycosaminoglycans covalently attached to plasma membrane– bound core proteoglycans Heparan sulfate comprises 50% to 90% of endothelial glycosaminoglycans The remainder is a mixture of hyaluronic acid, dermatan, keratan, and chondroitin sulfates.41 In healthy vessels, the EG determines vascular permeability, attenuates blood cell–vessel wall interactions, mediates shear stress sensing, enables balanced signaling, and fulfills a vasculoprotective role When the EG is disrupted or modified, these properties are lost (Fig 25.4) Evidence is emerging that damage to the glycocalyx plays a pivotal role in several vascular pathologies Interactions of Leukocytes With the Vessel Wall It is now well established that flowing leukocytes may adhere to specific regions of the endothelium in response to tissue injury or infection These multicellular interactions are essential precursors of physiologic inflammation Leukocytes interact with vessel surfaces through a multistep process that includes (1) initial formation of usually reversible attachments; (2) activation of the attached cells; (3) development of stronger, shear-resistant adhesion; and (4) spreading, emigration, and other sequelae36 (Fig 25.5) Selectins are key molecules in the interaction of leukocytes and endothelial cells They are transmembrane glycoproteins that recognize cell-surface carbohydrate ligands found on leukocytes and initiate and mediate tethering and rolling of leukocytes on the endothelial cell surface Selectins constitute a family of three known molecules L-selectin is expressed on most leukocytes and step model for leukocyte recruitment at sites of inflammation begins with the activation of neutrophils and endothelial cells Once activated, endothelial cells express selectins, whose binding to neutrophils initiates rolling and adhesion of neutrophils to the endothelium Activated integrins on the surface of neutrophils bind to endothelial cell intercellular adhesion molecules (ICAMs), facilitating a firm adhesion Transmigration through the endothelium further involves interactions with other molecules, such as platelet endothelial cell adhesion molecules and cadherins on the surface of endothelial cells binds to ligands constitutively expressed on endothelial cells found in venules of lymphoid tissues Its expression is induced on endothelium at sites of inflammation E-selectin is expressed on activated endothelial cells and leukocytes P-selectin is rapidly redistributed from secretory granules to the surface of platelets and endothelial cells stimulated with thrombin Both endothelial cell E-selectin and P-selectin bind to ligands on leukocytes.37 With stimulation, leukocytes usually attach to the glycocalyx of endothelial cells, where shear stresses are lowest Leukocytes adherent to the endothelium can make contact with flowing leukocytes through the L-selectin molecule, resulting in amplification of leukocyte recruitment to sites of inflammation It is generally understood that selectins initiate inflammatory, immune, and hemostatic responses by promoting transient multicellular interactions.42 Proinflammatory molecules presented on the surface of the endothelium proceed to activate a second family of adhesion molecules, the integrins, and cause cells to firmly adhere After the initial tethering of leukocytes to endothelial cells, leukocytes then must roll prior to transmigrating through the endothelium Inhibition of leukocyte adhesion does not reduce leukocyte rolling, suggesting that rolling and adhesion are distinct molecular events In addition, inhibiting rolling reduces adhesion, suggesting that rolling is a prerequisite of leukocyte adhesion/recruitment and, ultimately, the inflammatory response Leukocytes subsequently migrate between endothelial cells into tissues by mechanisms that are not completely understood but that we know are affected by gradients of chemokines, integrin activation states, and interactions with PECAM-1, an Ig-like receptor This migration requires disruption of endothelial-cellto-endothelial-cell interaction of cadherins at tight junctions Leukocyte recruitment to lymphoid tissues or inflammatory sites requires the coordinated expression of specific combinations of adhesion and signaling molecules Diversity at each step of the cascade ensures that the appropriate leukocytes accumulate for a restricted period in response to a specific challenge.4,42 CHAPTER 25 Endothelium and Endotheliopathy Platelet Adhesion Endothelial cells and circulating platelets normally not interact with each other due to the release of PGI2, release of NO, and expression of CD39 on the surface of endothelial cells.43 During vascular injury and inflammation, platelets adhere to exposed subendothelial components and are rapidly activated Circulating platelets interact with the adherent platelets, producing a hemostatic plug that promotes thrombin generation and development of a stable fibrin clot High shear stress, as seen in arteries, increases platelet adherence to the subendothelium where unactivated platelets attach to the subendothelium through interactions of platelet glycoproteins with immobilized von Willebrand Factor (vWF), a large multimeric protein with binding sites for several other molecules, including subendothelial collagen Flowing platelets attach transiently to vWF, resulting in continuous movement of the cells along the surface Under the lower shear stresses found in veins, unactivated platelets interact with integrins to attach to and immediately arrest on immobilized fibrinogen.44 Once platelets adhere to either vWF or fibrinogen, they are activated by secreted products, such as adenosine diphosphate or epinephrine or by surface molecules such as collagen that crosslink the integrins and other platelet receptors The activated platelets spread and adhere more avidly to the subendothelial surface, which recruits additional platelets into aggregates Shear-resistant adhesion may be further enhanced by interactions of other integrins or receptors with laminin, fibronectin, and thrombospondin As thrombin is generated, converting bound fibrinogen to fibrin, the aggregated platelets contract to strengthen the clot.44 Endothelial Permeability Maintenance of the integrity of the vascular endothelium is crucial for several physiologic functions, such as normal tissue fluid homeostasis, vessel tone, and host defense The vascular integrity and permeability barrier function is crucially supported by intercellular junctions between endothelial cells There are two major subtypes of endothelial intercellular junctions: tight junctions (or zona occludens) and adherens junctions (or zona adherens) In normal conditions, the barrier function of the vascular endothelium is properly regulated and vascular permeability is limited In vascular pathology, such as sepsis, proinflammatory signals activate endothelial cells, resulting in disruption and destabilization of the endothelial barrier.45,46 VE-cadherin is the major component of adherens junctions and is a tightly regulated protein complex that joins adjacent endothelial cells and prevents vascular leak (Fig 25.6) The displacement of VE-cadherin from the cell membrane to the interior of the cell induces gaps between endothelial cells, leading to increased permeability The disruption of the VE-adherens complex is prevented by another protein, p120catenin, which binds to and stabilizes VE-cadherin at the membrane Inflammatory mediators are known to cause p120-catenin and VE-cadherin to dissociate, resulting to internalization of VEcadherin Endothelial Cell Dysfunction Ischemia-Reperfusion Injury Reperfusion of previously ischemic tissues can place the organs at risk for further cellular injury, limiting the recovery of function The microvasculature, particularly the endothelial cells, is vulnerable to the deleterious consequences of ischemia and reperfusion 223 Cell junctions intact Lumen β-Catenin α-Catenin p120-catenin VE-cadherin Subendothelial space Cell junctions disassembly Vascular leak β-Catenin α-Catenin VE-caderin p120-catenin Interstitial edema • Fig 25.6 Inflammatory mediators induce gaps between endothelial cells by disassembly of intercellular junctions and disturbing the cytoskeleton The creation of gaps can result in microvascular leak and tissue edema Key in this process is the dissociation of p120-catenin from VE-cadherin in response to inflammatory mediators (I-R) I-R is now recognized as a potentially serious problem encountered during a variety of standard medical and surgical procedures, such as thrombolytic therapy, organ transplantation, and cardiopulmonary bypass.47 Hypoxia and inflammation are intimately linked on many levels and have functional roles in many human diseases Indeed, a wide range of clinical conditions are characterized by hypoxiaor ischemia-driven inflammation or by inflammation-associated hypoxia The molecular and biochemical changes in the vascular wall during I-R are characteristic of an acute inflammatory response (Fig 25.7) The intensity of this inflammatory response can be so severe that the injury response to reperfusion is also manifested in susceptible organs, such as the lungs and cardiovascular system The resulting systemic inflammatory response syndrome (SIRS) and multiple-organ dysfunction syndrome (MODS) are both associated with significant increases in mortality and morbidity.48 Microvascular dysfunction associated with I-R is manifested as impaired endothelium-dependent dilation in arterioles, enhanced 224 S E C T I O N I V Pediatric Critical Care: Cardiovascular Sepsis Ischemia/ reperfusion Immune complexes Systemic mediator release Neutrophil activation and adhesion molecule expression Endothelial activation and adhesion molecule expression Neutrophil-endothelial cell interaction: Tethering, rolling, adhesion, transmigration Endothelial cell dysfunction Neutrophil-mediated remote organ vascular dysfunction Endothelial cell–mediated vascular dysfunction Tissue injury • Fig 25.7 Mechanisms that underlie the development of local and remote organ injury following an initial inflammatory event The activation of endothelial cells and circulating neutrophils leads to the expression and activation of adhesion molecules that facilitate neutrophil invasion of vascular beds, resulting in local and remote organ dysfunction fluid filtration, leukocyte plugging in capillaries, and the trafficking of leukocytes and plasma protein extravasation in postcapillary venules During the initial period following reperfusion, activated endothelial cells in the microcirculation produce more oxygen radicals and less NO The resulting imbalance between superoxide and NO in endothelial cells leads to the production and release of inflammatory mediators (e.g., platelet-activating factor, TNF-a) and enhances the biosynthesis of adhesion molecules that mediate leukocyte–endothelial cell adhesion.48 Since its discovery in the early 1990s, hypoxia-inducible factor (HIF1) has been increasingly recognized for its key role in transcriptional control of more than 100 genes that regulate a wide spectrum of cellular functional events, including angiogenesis, vasomotor control, glucose and energy metabolism, erythropoiesis, iron homeostasis, pH regulation, cell proliferation, and viability Animal studies have provided compelling data to demonstrate a pivotal role for the HIF pathway in the pathogenesis of ischemic injury For example, HIF1a has been shown to play a role in mediating cardioprotection.49 The inflammatory mediators released as a consequence of reperfusion also appear to activate endothelial cells in remote organs that are not exposed to the initial ischemic insult Oxidants and activated leukocytes have been implicated as mediators of remote organ injury in I-R This distant response to I-R can result in leukocyte-dependent microvascular injury that is characteristic of SIRS and MODS The pulmonary damage associated with MODS can range from mild dysfunction to severe failure, as in acute respiratory distress syndrome (ARDS) The pulmonary injuries associated with ARDS include increased pulmonary microvascular permeability and the accumulation of neutrophil-rich alveolar fluid Respiratory failure often is associated with cardiovascular, hepatic, gastrointestinal, and renal dysfunction as well as central nervous system involvement MODS is associated with dysfunction of the coagulation cascade and immune system, resulting in thrombosis, disseminated intravascular coagulation, and immunocompromise The initiation of MODS may also lead to further tissue ischemia, resulting in additional insult.50 Sepsis Although the pathophysiologic process of multiple organ dysfunction during sepsis is multifactorial, one common feature is the dysfunction of the microcirculation, including the resistance of arteries, capillaries, and postcapillary venules The microcirculation cannot be considered a simple passive conduit Rather, it is a functionally active system of interactions among the vascular wall; circulating and tissue-associated cells, such as leukocytes, platelets, and mast cells; and extracellular mediators that contribute to the regulation of local, downstream, and upstream vascular tone Sepsis is particularly associated with microvascular endothelial cell dysfunction leading to (1) the breakdown of endothelial barrier function, leading to tissue edema and uncontrolled inflammatory cell infiltration; (2) vasomotor dysfunction, leading to the formation of arteriovenous shunts in association with loss of peripheral resistance; and (3) disturbance of oxygen transport and utilization by tissue cells.51 Another major mechanism during sepsis is the change from anticoagulant to procoagulant and the contribution of microthrombi to the disturbance of the microcirculation Lipopolysaccharide, an important pathogen product, is recognized by pathogen recognition receptors such as toll-like receptors on cells of the innate immune system This will lead to intracellular signaling and to the production of cytokines and other potent chemokines Septic shock is often associated with the loss of fluid from the intravascular into the extravascular space with the potential progressive loss of circulating blood, eventually leading to a depression of cardiac output Similarly, loss of fluid into the extravascular space can lead to life-threatening edema in the lungs, kidney, and brain of septic patients The loss of fluid is not believed to be associated with changes in hydrostatic or osmotic pressures within the vascular compartment but rather to the breakdown of endothelial barrier function The permeability of the vascular barrier can be modified in response to specific stimuli acting on endothelial cells Many inflammatory agonists mediate endothelial hyperpermeability via a calcium-dependent mechanism Multiple cascades of intracellular signaling reactions are initiated when an inflammatory agonist binds to its respective receptor expressed on the endothelial surface (e.g., thrombin binds the protease-activated receptor-1, histamine binds its receptor H1, and vascular endothelial growth factor binds its vascular endothelial growth factor receptor [VEGFR-2]) This breakdown allows migration of water and macromolecules, including proteins, into the extravascular space The pathophysiologic mechanisms proposed include the separation of tight junctions between endothelial cells, as well as cytoskeleton contraction, rather than destructive changes of endothelial cells leading to defects in the endothelium.44,52 Studies on the microcirculation of the gut have shown the development of a gap between microvascular and venous oxygen tension, suggesting enhanced shunting of the microcirculation Defects in distributing blood to regional vascular beds or the microcirculation could be responsible for tissue hypoxia and limited oxygen extraction Clinical evidence of decreased microvessel CHAPTER 25 Endothelium and Endotheliopathy 225 density in the sublingual microcirculation of fluid-resuscitated septic patients is consistent with findings of decreased functional capillary flow in the gut, liver, and skeletal muscle microcirculation in animal models of sepsis This clinical finding raises the possibility that abnormal microvascular oxygen transport develops in multiple organs despite fluid resuscitation, leading to heterogeneous microvascular dysfunction and local tissue hypoxia in severe cases of sepsis in the interactions with endothelial cells belong to three major families: selectins, sialomucins, and integrins Interestingly, it is recognized that these interactions participate in tissue specificity in various vasculitic conditions For instance, specific selectin interactions mediate cutaneous tropism in several inflammatory disorders, including graft-versus-host disease and dermatomyositis.55 Hemolytic-Uremic Syndrome There is a strong rationale for targeting markers of endothelial cell activation as clinically informative biomarkers to improve diagnosis, prognostic evaluation, or risk stratification of critically ill patients During sepsis, a large number of endothelial cell–active molecules are potential biomarkers for the early diagnosis These include regulators of endothelial activation, such as vascular endothelial growth factor (VEGF), the angiopoietin pathway (Ang-1/2), adhesion molecules (intercellular adhesion molecule [ICAM], vascular cell adhesion molecule [VCAM], and E-selectin), mediators of permeability and vasomotor tone (ET-1), and mediators of coagulation (e.g., vWF).56 Elevated endothelin levels have been found in systemic and pulmonary hypertension, coronary artery disease, and heart failure, although the role of ET-1 in the pathophysiology of these conditions has been postulated but not proved.57,58 Cellular markers such as EPCs and endothelial microparticles (EMPs) are also gaining interest as biomarkers There is a positive correlation between EPC number and survival in sepsis.59 In addition, there is a functional impairment of EPCs with decreased proliferative and migratory capacities of EPCs These findings have led to therapeutic strategies (e.g., statins) that focus on improving EPC number and function during sepsis.60 In contrast, an elevation of EMPs is considered a marker of endothelial dysfunction in cardiovascular disease However, the number of EMPs is positively related to survival and inversely correlated with the Sequential Organ Failure Assessment (SOFA) score in patients with sepsis Because it is becoming increasingly clear that microparticles are more than simple markers of endothelial damage or activation, their interpretation as markers of endothelial dysfunction is less ambiguous.61 Interestingly, EPCs show a biphasic response after traumatic brain injury; after an initial decrease, they peak days after the insult Furthermore, they have been associated with an improved outcome after traumatic brain injury.62 However, the clinical utility of these biomarkers is limited by a lack of assay standardization, unknown receiver operating characteristics, and lack of validation In addition, evidence is lacking that these biomarkers are associated with endothelial cell and vascular tone dysfunction It remains speculative whether the use of endothelial cell biomarkers will guide therapy during critical care illness in the near future Thrombotic thrombocytopenic purpura (TTP) and the hemolytic uremic syndrome (HUS) are related disorders characterized clinically by microangiopathic hemolytic anemia and thrombocytopenia Pathologically, both conditions include the development of platelet microthrombi that occlude small arterioles and capillaries Endothelial dysfunction plays a prominent role in the pathogenesis of both disorders HUS commonly occurs in early childhood (≈90% of cases) It often follows an episode of bloody diarrhea caused by enteropathic strains of Escherichia coli that release an exotoxin, verotoxin-1 (VT-1; see also Chapter 75) VT-1 binds with high affinity to receptors expressed in high density on renal glomerular endothelial cells VT-1 is directly cytotoxic to endothelial cells, where it promotes neutrophil-mediated endothelial cell injury VT-1 induces the production of TNF-a by monocytes and cells within the kidney In turn, TNF-a, in synergy with interleukin-1, increases VT-1 receptor expression and exacerbates the sensitivity of the endothelium to toxin-mediated and antibody-mediated cytotoxicity It also promotes vWF release and impairs fibrinolytic activity.53 There is considerable evidence to suggest that endothelial cell injury plays a role in the pathogenesis of TTP Platelet microthrombi in TTP contain abundant vWF but little fibrinogen in contrast to those seen in disseminated intravascular coagulopathy A subgroup of patients has been identified who suffer from chronic, relapsing TTP and whose plasma continues to contain elevated levels of unusually large vWF multimers (ULvWFs) between relapses ULvWFs may exacerbate microvascular thrombosis through their ability to aggregate platelets at high levels of shear stress The secretion of ULvWF by cultured endothelial cells is stimulated by many agonists, including Shiga toxin However, elevated levels of vWF occur in other thrombotic microangiopathies; their exact role in TTP/HUS requires further study Endothelial damage plays a pivotal role in the pathogenesis of the disease The events that initiate TTP remain unknown More recently, plasma from patients with TTP and HUS has been reported to induce apoptosis in microvascular endothelial cells Interestingly, cells from dermal, renal, and cerebral origin were most susceptible, whereas pulmonary and coronary arterial cells were less susceptible.54 Vasculitic Disorders Vasculitis is a disease that targets all levels of the arterial tree, from aorta to capillaries It also affects venules, with leukocyte infiltration and necrosis Different forms of vasculitis attack different vessels and are classified accordingly The inflammatory process may target vessels of any type throughout the vascular system, although distinct clinicopathologic entities preferentially involve vessels of particular sizes and locations Small vessels anywhere in the body may be affected by focal necrotizing lesions where extravasation of leukocytes drives the inflammatory responses, resulting in vasculitis Leukocyte adhesion molecules participating Biomarkers of Endothelial Activation Conclusions The endothelium can no longer be viewed as a static physical barrier that simply separates the blood from tissue Rather, the endothelium coordinates key functions of different tissues in normal and pathophysiologic conditions This is accomplished by the interaction of endothelial cells with circulating factors and cells and its ability to transmit biochemical and biophysical signals to surrounding tissues A greater understanding of endothelial physiology will lead to novel therapeutic approaches in complex clinical conditions ... gradients of chemokines, integrin activation states, and interactions with PECAM-1, an Ig-like receptor This migration requires disruption of endothelial-cellto-endothelial-cell interaction of cadherins... the cytoskeleton The creation of gaps can result in microvascular leak and tissue edema Key in this process is the dissociation of p120-catenin from VE-cadherin in response to inflammatory mediators... wall during I-R are characteristic of an acute inflammatory response (Fig 25.7) The intensity of this inflammatory response can be so severe that the injury response to reperfusion is also manifested