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tefanec, MD* From the Section of Critical Care Medicine, Saint Vincent Hospital and Medical Center, New York, NY.
Correspondence to: Tihomir tefanec, MD, Pulmonary Service, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; e-mail: stefanet{at}mskcc.org
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Abstract |
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 TOP Abstract IntroductionEndothelial Pro- and...Changes Accompanying Endothelial...Circulating Endothelial CellsRole of Endothelial Apoptosis...Conclusion and Future ProspectsReferences |
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Key Words: apoptosis • atherosclerosis • endothelium • heart failure • hypertension • primary pulmonary hypertension • sepsis
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Introduction |
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TOPAbstractIntroductionEndothelial Pro- and...Changes Accompanying Endothelial...Circulating Endothelial CellsRole of Endothelial Apoptosis...Conclusion and Future ProspectsReferences |
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Endothelial Pro- and Antiapoptotic Stimuli |
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TOPAbstractIntroductionEndothelial Pro- and...Changes Accompanying Endothelial...Circulating Endothelial CellsRole of Endothelial Apoptosis...Conclusion and Future ProspectsReferences |
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12 h and
apoptosis becomes maximal at 18 h, to be replaced by a
predominantly necrotic form of cell death after 24 h of
exposure.67
85
Fourth, a stimulus may initiate changes in
endothelial cells that have opposing effects on the activation of
apoptosis. LPS can, for example, activate the transcription of
antiapoptotic factors produced by endothelial cells
themselves,93
and the intracellular balance of several
opposing influences likely determines the activation of the apoptotic
cascade of caspases. Fifth, the nature, strength, and duration of
exposure to a given combination of pro- and antiapoptotic stimuli
could perhaps determine the clinical picture by causing a specific
distribution and extent of endothelial apoptosis; this may lead, on one
end of the spectrum, to localized and low-grade vascular changes that
slowly progress over several decades,7
and could on the
other cause widespread apoptosis of a majority of endothelial cells,
leading to death within hours to days.37 The endothelium shows little evidence of perturbation in the absence of disease. If specifically searched for, apoptotic endothelial cells are rarely found in the intima of vessels that show no evidence of vascular disease.7 Illustrative of this can be the fact that the normal human circulation contains an average number of 2.6 circulating nucleated endothelial cells per milliliter of blood.94 At least 60% of them were found to be apoptotic95 using a method that is not sensitive for the earliest changes accompanying apoptosis.96 The number of approximately 10,000 circulating nucleated endothelial cells (or even one that may be 100 to 1,000 times higher, if one could count all anuclear endothelial cell fragments94 or apoptotic bodies) in a blood volume of 3.5 to 4 L is negligible compared with the total number of endothelial cells (> 1013). This suggests that under normal resting conditions, a predominance of antiapoptotic factors maintains the percentage of apoptotic cells at a very low level (< 0.1% in the control group of an animal study29 ). These facts can, at least in part, explain the notorious difficulty in detecting a rare and short-lasting event like apoptosis, in the section of a layer of tissue as thin as the endothelium, especially if it has not been specifically searched for.
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Changes Accompanying Endothelial Apoptosis |
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TOPAbstractIntroductionEndothelial Pro- and...Changes Accompanying Endothelial...Circulating Endothelial CellsRole of Endothelial Apoptosis...Conclusion and Future ProspectsReferences |
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B
(NF-B).74
80
98
While activation of NF-B may protect
the endothelial cell from apoptosis91
in an environment
that is likely to be predominantly proapoptotic, it also leads to the
expression and release of adhesion molecules for inflammatory cells and
production of proinflammatory cytokines.98
Leukocytes may
adhere, transmigrate, release proteases, cause additional endothelial
injury, and lead to the development of inflammatory changes in the
vessel wall. Release of adhesion molecules prevents further leukocyte
adherence,99
but may at the same time cause leukocyte
activation and lead to release of additional proinflammatory mediators
or proteases,100
101
thereby giving rise to endothelial
injury or apoptosis in nearby or distant endothelial surfaces. The
exact nature of soluble adhesion molecule production and release by
endothelial cells is presently insufficiently understood; both
proteolytic cleavage of membrane-bound forms as well as messenger RNA
encoding soluble adhesion molecules have been described in
nonendothelial cells. It has been suggested that mediators other than
IL-1 participate in the above events.74
80
Messenger RNA
for several pro- and anti-inflammatory mediators has been found in
resting and stimulated endothelial cells,102
and secretion
of TNF by the endothelium has been demonstrated in
vitro.103
Whether release of these mediators
participates in the events associated with endothelial apoptosis is
presently unknown. The mitochondrion plays a key role in the initiation and amplification of the apoptotic process.104 During apoptosis, it releases cytochrome c, which disrupts its electron transport chain. While normal oxidative phosphorylation loses some 1 to 5% of electrons to superoxide production, this percentage increases with loss of cytochrome c from the mito-chondria of the apoptotic cell.104 105 The freely diffusible nitric oxide (NO) and newly produced superoxide form peroxynitrite, itself a toxic and proapoptotic substance for the endothelium.77 NO is consumed in this reaction and is not available for its normal role in vasodilatation, inhibition of platelet aggregation, and prevention of endothelial apoptosis, as well as inhibition of vascular smooth muscle cell proliferation and leukocyte adhesion.1 72 106
Normal anticoagulant properties of vascular endothelium are lost during apoptosis. The surface of the apoptotic cell exhibits increased tissue factor procoagulant activity, as well as reduced surface thrombomodulin, heparan sulfate, and tissue factor pathway inhibitor expression.96 This leads to increased thrombin formation by both adherent and detached apoptotic endothelial cells. Prostacyclin production is decreased during endothelial apoptosis.107 This may, apart from a reduced antiapoptotic effect,90 lead to loss of inhibition of platelet activation.1 Both activated platelets and thrombin can enhance inflammatory and proapoptotic events through activation of leukocytes and endothelial cells.108 109
Complement activation via the alternative pathway has been observed on apoptotic endothelial cells.110 While this activation may enhance the clearance of apoptotic cells by phagocytes, it can also activate leukocytes and endothelial cells, and mediate additional endothelial injury or apoptosis.
Not only does endothelial apoptosis lead to the just described changes, but these changes may also, if induced through other mechanisms, lead to apoptosis of the endothelium (Fig 1) . To complicate matters further, some inflammatory changes may have pro- and antiapoptotic effects. For example, monocytes can release the proapoptotic TNF but may, in direct contact with the endothelium, prevent apoptosis of its cells in a proapoptotic environment.81 Neutrophils secrete TNF and proapoptotic proteases, but also release the antiapoptotic vascular endothelial growth factor (VEGF), as well as the anti-inflammatory and likely antiapoptotic IL-1 receptor antagonist (IL-1 Ra).71 111 112 113 These mechanisms may serve to limit the intensity of proinflammatory and apoptotic changes, and prevent their extension to previously unaffected areas of the vasculature.
Adrenomedullin and endothelin-1 levels are elevated in circumstances associated with endothelial perturbation (Table 1) . They have opposite effects on vascular tone; endothelin-1 is one of the most potent vasoconstrictors, whereas adrenomedullin causes vasodilatation. Both were found to have an autocrine/paracrine antiapoptotic effect on endothelial cells.86 89 Their secretion in circumstances associated with endothelial injury, activation, and apoptosis is controlled independently,114 and may represent a mechanism that limits endothelial damage and enhances its recovery, while adjusting vascular tone and blood flow in the distribution of disturbed endothelial-derived vasomotor control.
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Circulating Endothelial Cells |
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TOPAbstractIntroductionEndothelial Pro- and...Changes Accompanying Endothelial...Circulating Endothelial CellsRole of Endothelial Apoptosis...Conclusion and Future ProspectsReferences |
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Role of Endothelial Apoptosis in Disease |
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TOPAbstractIntroductionEndothelial Pro- and...Changes Accompanying Endothelial...Circulating Endothelial CellsRole of Endothelial Apoptosis...Conclusion and Future ProspectsReferences |
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Atherosclerosis
Apoptotic endothelial cells have been demonstrated in experimental
and human atherosclerosis.6
7
Practically all risk factors
for atherosclerosis either cause endothelial apoptosis in
vitro or increase the number of circulating endothelial cells
in vivo, and some protective factors have the opposite
effect (Tables 2 , 3)
. Many interventions known to be effective in the
prevention or treatment of atherosclerosis and its complications may in
some way reduce apoptosis of the endothelium (Table 4
).124
125
126
127
128
129
130
131
132
133
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The earliest observed alterations in the vessel wall are the fatty streak and monocyte adhesion. The endothelium oxidizes native LDL in a mitochondrial-dependent fashion.124 This is likely to be enhanced in the presence of increased superoxide production by the mitochondria of the apoptotic endothelial cells, and may not be dependent on an increased availability of LDL. Oxidized LDL is one of the best-described endothelial proapoptotic agents, and apoptosis could amplify itself in this manner. Interestingly, adherent monocytes are antiapoptotic for the endothelium when the latter is exposed to a proapoptotic environment.81 They have also been observed to enter and leave the subendothelial space.136 Active endothelial participation is required for monocyte adhesion and transmigration to the subendothelium, and one of the first observable changes associated with this process is the expression of endothelial adhesion molecules for mononuclear leukocytes.1 2 The early accumulation of monocytes could therefore represent an attempt by the endothelium to reduce the proapoptotic activity of the subendothelial oxidized LDL and assist in its removal. Indeed, it has been hypothesized that the advancement of the atherosclerotic lesion may be occurring as a result of a failure of this monocyte clearance system to remove sufficient lipid.136
Platelet-derived growth factor and endothelin-1 cause vascular smooth muscle cell proliferation and are released in some circumstances associated with endothelial apoptosis.2 114 137 Angiotensin II and a reduced availability of NO favor apoptosis in endothelial cells.50 72 The exact opposite occurs with smooth muscle cells; their apoptosis is inhibited and proliferation enhanced by angiotensin II and the absence of NO.106 This indicates that endothelial apoptosis could be associated with vascular smooth muscle cell proliferation, and smooth muscle cells are an important component of the atherosclerotic plaque.
Both macrophages and smooth muscle cells in the atherosclerotic plaque can produce TNF138 and could thereby cause additional apoptosis of the overlying endothelium. Endothelial-derived mediators may be able to activate cells in the plaque.74 102 A positive feedback mechanism established in this way could lead to a rapid acceleration of plaque growth. Mediators released in systemic infections and inflammatory processes could lead to an enhancement of endothelial apoptosis and proinflammatory activity inside the atherosclerotic lesion, explaining the well-known association between symptomatic atherosclerosis and systemic inflammation.139 In times of predominance of endothelial antiapoptotic stimuli, a reversal of the above process could lead to smooth muscle and inflammatory cell apoptosis,91 allowing a reduction of inflammatory changes and possibly even plaque size. The remnants of these cells can accumulate in the depth of the plaque,140 and if this process occurs repeatedly through several decades, it could contribute to the formation of high-grade stenotic lesions.
It is difficult to separate endothelial injury and activation from the presence of endothelial apoptosis (Table 1 , Fig 1 ) and soluble markers of endothelial injury or activation could perhaps be viewed as surrogate markers for the presence of endothelial apoptosis. This could explain the observation that soluble endothelial adhesion molecules correlate with the risk of symptomatic atherosclerosis,5 and that effective antiapoptotic therapeutic approaches8 reduce markers of endothelial injury.141 Interestingly, some soluble endothelial adhesion molecules show a diurnal variation in healthy humans,142 indicating that mechanisms of endothelial activation or apoptosis might cause the well-documented increased frequency of acute coronary syndromes at certain times of the day.
Allograft Vasculopathy
Endothelial apoptosis was demonstrated in human transplant
coronary artery disease, and is thought to be caused by cytotoxicity
induced by cytolytic T cells.7
15
While endothelial
changes remain restricted to certain vascular segments in nontransplant
atherosclerosis, vessels in transplanted organs are affected diffusely
and show vasculitic changes.7
143
Similar to in
nontransplant atherosclerosis, the endothelium shows evidence of
dysfunction and activation.13
14
These changes may be an
early marker for the severity of allograft vasculopathy and risk of
graft failure.14
Calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors, and statins have demonstrated some effect in slowing the progression of allograft vasculopathy,143 all of them possibly through their antiapoptotic effect on the endothelium (Table 4) . Cyclosporin A has shown similar results143 ; apart from its beneficial immunosupressive effect, it prevents mitochondrial membrane dysfunction and cytochrome c release, and reduces endothelial apoptosis induced by oxidized LDL, TNF, and angiotensin II in vitro50 (in a model of nontransplant atherosclerosis, it reduced the formation of plaques in vivo144 ).
Hypertension
Hypertension is characterized by capillary rarefaction, a
reduction of the number of capillaries per volume of tissue. This
rarefaction can be found in young hypertensives and may have a
hereditary component.145
In the established Goldblatt
model of hypertension, microvascular rarefaction occurs through
apoptosis of the endothelium.21
Capillary rarefaction was
less pronounced in female rats,146
which could be related
to the antiapoptotic effects of estradiol.
Hypertension itself may have a proapoptotic effect on some cell types in vitro,147 and causes endothelial dysfunction accompanied by increased superoxide production148 ; the latter findings are consistent with endothelial apoptosis. Elevated angiotensin II and natriuretic peptides149 may contribute to endothelial apoptosis. Many treatments used in hypertension also have a direct or indirect antiapoptotic effect (Table 4) .
Congestive Heart Failure
In an animal model of aortic insufficiency, increased numbers of
circulating endothelial cells were found 28 days after the induction of
the hemodynamic abnormality, and this rise was prevented by
administration of an ACE inhibitor.30
In a model of
monocrotaline-induced right ventricular failure in rats, the number of
apoptotic endothelial cells in skeletal muscle showed a progressive and
statistically significant increase over a period of 30
days.29
These changes were accompanied by an increase in
TNF and atrial natriuretic peptide, and the increase in atrial
natriuretic peptide showed a significant correlation with the number of
apoptotic endothelial and myocyte nuclei.29
Of note,
apoptosis of endothelial cells preceded myocyte apoptosis in this
model, which led the authors to conclude that ischemia due to damage or
decrease in the number of capillaries may have contributed to the
observed myofiber loss. If present in the myocardium, such a process
could contribute to the observed apoptosis of
cardiomyocytes.91
Monocrotaline itself causes endothelial
apoptosis in vitro, but it appears unlikely that it
contributes to such an effect in vivo several weeks after
the administration of a single dose.
TNF, natriuretic peptides, angiotensin II, and a reduction of shear stress may contribute to endothelial apoptosis in human congestive heart failure (CHF). Some therapies utilized in CHF could derive part of their benefit from a reduction of endothelial exposure to proapoptotic factors (Table 4) . Digoxin may have a "stabilizing" effect on endothelial cells.122 Carvedilol reduces oxidation of LDL by endothelial cells and prevents endothelial dysfunction in vivo under conditions that are proapoptotic for the endothelium.150 151 This suggests that its beneficial effect may, in part, be related to a prevention of endothelial apoptosis. Interestingly, in a recent study in patients with ischemic left ventricular dysfunction, carvedilol showed the greatest benefit in the subgroup of patients with elevated proapoptotic natriuretic peptides in combination with lower norepinephrine levels,152 suggesting that a possibly present antiapoptotic effect may be of greater importance than its known sympatholytic action.
Sepsis and Associated Syndromes
For the purpose of this discussion, sepsis and associated
syndromes includes systemic inflammatory response syndrome, ARDS,
and multiple organ dysfunction syndrome.
Endotoxin has been shown to lead to endothelial injury by causing detachment of endothelial cells from the basal membrane, resulting in an increase in the number of circulating endothelial cells in vivo.33 LPS, TNF and cecal ligation and puncture have been shown to cause endothelial apoptosis in vivo, in association with syndromes that were consistent with sepsis and acute lung injury.36 37 38
Age, extracellular adenosine triphosphate, angiotensin II, infectious agents and their cellular components, hyperglycemia, osmolar stress, ischemia/reperfusion, IL-1, intracellular acidosis, natriuretic peptides, neutrophil proteases, transforming growth factor ß1, hypoalbuminemia, decreased antioxidant levels, hypovolemia with an associated hypodynamic state leading to a reduction of shear stress, and possibly other factors may contribute to endothelial apoptosis during the inflammatory response to tissue injury or infection (Table 2) . The body’s own anti-inflammatory responses—in the form of soluble TNF receptors, IL-1 Ra, and interleukin 10 release—as well as the development of a hyperdynamic state and the expression of inducible nitric oxide synthase (NOS) in endothelial cells, may help to limit exposure to proapoptotic factors and provide some antiapoptotic stimuli for the endothelium.
Endothelial activation is an integral component of the inflammatory response to tissue injury and infection. It leads to the release of adhesion molecules and their levels correlate with presence of infection, disease severity, and outcome.34 Endothelial IL-1 and adhesion molecule release, leukocyte activation, and the presence of many of the above-mentioned proapoptotic factors could lead to a dissemination of endothelial activation, apoptosis, and injury, potentially transforming an initially local reaction into a systemic event. Disseminated intravascular coagulation, diffuse microvascular injury and obstruction, increased vascular permeability, perfusion failure, and organ dysfunction in sepsis and the associated syndromes may be related in part to widespread endothelial apoptosis.
Very few therapies utilized in clinical practice are capable of reducing endothelial apoptosis in sepsis, which might partially explain the absence of any significant impact on the outcome of this syndrome despite many years of trials testing anti-inflammatory therapies. Most of the available "antiapoptotic" therapies show a benefit, but remain experimental and are not widely accepted.
Supranormal oxygen delivery is a controversial form of treatment, based on an equally controversial assumption of abnormal oxygen consumption in sepsis. It has shown some benefit when applied prophylactically, before the onset of septic shock or organ dysfunction.153 Its beneficial effect could be related to an antiapoptotic effect of increased shear stress72 85 and to the prevention of adhesion of leukocytes to the endothelium.154 Both mechanisms may not work if applied too late in the course of disease, when diffuse endothelial injury has already occurred.
The administration of an ACE inhibitor as a low-dose continuous infusion over 5 days to patients with sepsis led to a reduction of soluble markers of endothelial activation and injury, improved oxygenation, reduced neutrophil counts and lactate levels, and decreased incidence of septic shock, and showed a trend toward reduced mortality in a relatively small number of patients.155 These benefits may be related to the documented reduction of the proapoptotic angiotensin II.
Prostacyclin is an endothelial-derived antiapoptotic agent, the normal functions of which include vasodilatation and platelet inhibition.1 2 Its secretion is reduced in endothelial apoptosis.108 When administered by inhalation, it has effects similar to those of inhaled NO: lowering pulmonary artery pressures and improving oxygenation, but leading additionally to enhanced splanchnic perfusion.156 157 A recent multicenter trial evaluated the use of ibuprofen in patients with sepsis. This compound led to a reduction in prostacyclin production, and showed no significant effects on outcome.158 The beneficial effect of cyclooxygenase inhibition may have been outweighed by the negative effects of inhibited prostacyclin production.
Several other therapies deserve to be mentioned in this context. (1) Antiapoptotic antioxidants have shown some success in ameliorating the inflammatory processes in sepsis.159 (2) An experimental model demonstrated an impressive success of the antiapoptotic fibroblast growth factor (FGF) in reducing mortality associated with lethal endotoxemia.37 FGF has been given to humans for other indications, and has not demonstrated prohibitive side effects.132 (3) Reduced levels of the antiapoptotic VEGF have been found in association with severe complications like sepsis or ARDS in patients with burns and trauma.160 Reduced secretion of this endothelial survival factor may have contributed to the severity of disease, and its administration in such circumstances could perhaps lead to enhanced endothelial stability and a reduction in tissue injury. Minor side effects have been encountered during VEGF use in human atherosclerosis.133
Available data suggests that benefits of any such antiapoptotic therapy appear less likely if it is applied late in the course of disease or in the form of a single agent. The large number of proapoptotic factors present in sepsis and the associated syndromes will probably require a combined blockade of several apoptotic pathways, as well as the use of antiapoptotic endothelial growth factors in order to show a benefit in a process as rapid and currently irreversible as fulminant septic shock.
Primary Pulmonary Hypertension
A number of findings associated with primary pulmonary
hypertension (PPH) are consistent with a role of endothelial apoptosis
in its pathogenesis. Endothelial apoptosis has been demonstrated in
experimental PPH.43
Serum levels of IL-1ß are elevated
in human PPH,161
and treatment with an IL-1 Ra prevents
its development in an animal model of PPH.162
Prostacyclin
production is decreased,163
there is evidence of
endothelial dysfunction,42
and elevated markers of
endothelial injury are reduced during treatment with the antiapoptotic
prostacyclin.41
A number of different endothelial proapoptotic factors could contribute to the development of PPH and perhaps explain the variety of histopathologic patterns found in this disease.164 (1) ACE immunoreactivity is significantly increased in the endothelium and subendothelial regions of patients with PPH165 ; increased angiotensin II production may cause increased endothelial apoptosis50 and provide a proliferative stimulus for vascular smooth muscle cells.106 (2) Endothelial constitutive NOS (cNOS) is reduced in human PPH166 and its experimental reduction causes pulmonary hypertension in response to hypoxia in mice.167 A diminished baseline release of NO by the endothelium leads to the reduction of an important endothelial antiapoptotic stimulus and allows enhanced smooth muscle cell growth.72 106 (3) Antiphospholipid and antinuclear antibodies are frequently found in association with PPH168 169 ; the lupus anticoagulant and anti-double-stranded DNA antibody are proapoptotic for the endothelium.52 69 (4) Lack of estrogen receptors was found in the lung of a woman with PPH.170 Human lung tissue metabolizes estrogens and participates in the production of estradiol.171 A defect in this production could deprive the endothelium of an antiapoptotic substance. Furthermore, some circumstances may lead to an increased production of the proapoptotic 2-methoxyestradiol,172 but whether or not this occurs in the lung is presently unknown. (5) Increased release of the proapoptotic atrial natriuretic peptide45 and (6) the presence of hypoxia173 could exacerbate apoptosis of the endothelium in PPH.
Treatments for PPH include prostacyclin and calcium channel blockers.173 ACE inhibitors have shown some success in preventing vascular remodeling in an animal model of PPH.174 All have an antiapoptotic effect on the endothelium (Table 4) . Oxygen and diuretics may reduce some proapoptotic influences (hypoxemia and natriuretic factors131 ). Anticoagulation reduces thrombin generation and platelet activation, and could thereby have an indirect effect on endothelial apoptosis (Fig 1) .
Other Diseases
Endothelial apoptosis has also been demonstrated in systemic
sclerosis,51
diabetes,175
and thrombotic
thrombocytopenic purpura176
; it may play a role in
systemic lupus erythematosus,52
the antiphospholipid
antibody syndrome,68
development of
metastasis,82
and treatment of
cancer.49
54
61
62
Although there is no direct evidence of
endothelial apoptosis in preeclampsia, the presence of numerous other
findings177
suggest a possible role. A more detailed
discussion of these diseases is beyond the scope of this review.
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Conclusion and Future Prospects |
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TOPAbstractIntroductionEndothelial Pro- and...Changes Accompanying Endothelial...Circulating Endothelial CellsRole of Endothelial Apoptosis...Conclusion and Future ProspectsReferences |
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Although it cannot be considered proven at this time, the available data point to endothelial apoptosis as the final common pathway through which various insults could contribute to the development of certain diseases. Such a possibility is an opportunity too good not to be taken seriously. The endothelium is ideally positioned and widely exposed to circulating blood. Endothelial cells are easy to collect, culture, and study. Endothelial precursors may be able to provide us with information about individual predisposition to the development of some diseases. Already known pro- and antiapoptotic agents with good side-effect profiles could be evaluated, alone or in combination, as therapeutic agents in a variety of conditions. New pro- and antiapoptotic stimuli are likely to be found in the future and could be tested for their relevance in different diseases. More work in elucidating the mechanisms of apoptosis in endothelial cells needs to be done before we can embark on the path of drug therapy manipulating these processes in ill human beings, but we could be able to do just that by the end of the first decade of the new millennium.
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Acknowledgements |
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Footnotes |
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B = nuclear factor B;
NO = nitric oxide; NOS = nitric oxide synthase; PPH = primary
pulmonary hypertension; TNF = tumor necrosis factor;
VEGF = vascular endothelial growth factor Received for publication April 19, 1999. Accepted for publication September 8, 1999.
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References |
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TOPAbstractIntroductionEndothelial Pro- and...Changes Accompanying Endothelial...Circulating Endothelial CellsRole of Endothelial Apoptosis...Conclusion and Future ProspectsReferences |
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