Apoptosis in vascular disease

Eur J Vasc Endovasc Surg 22, 389–395 (2001)
doi:10.1053/ejvs.2001.1492, available online at http://www.idealibrary.com on
Apoptosis in Vascular Disease
T. C. F. Sykes∗1,2, A. G. Morris1, A. W. Bradbury2 and D. Mosquera2
1Biological Sciences, University of Warwick, Coventry CV4 7AL, 2Department of Vascular Surgery, Birmingham Heartlands Hospital, Birmingham B9 5SS, U.K. process may offer novel avenues for therapeutic inter- Apoptosis, or programmed cell death, was first de- scribed by Kerr et in 1972 as a specific type of cell death morphologically distinct from necrosis. Apo- Molecular Aspects of Apoptosis
ptotic cells undergo shrinkage with nuclear con- densation and the formation of membrane-bound Since the original morphological description of apo- vesicles called apoptotic bodies. These are phago- ptosis many molecular mechanisms that characterise cytosed by adjacent cells and macrophages without the apoptotic pathway have been identified. Apoptosis inducing an inflammatory response. In contrast, nec- is controlled by a well-ordered cascade of cellular rotic cells sustain membrane damage leading to the events that may be divided into four stages (initiation, release of pro-inflammatory intracellular contents. control/execution, structural/morphological al- Apoptosis although recognised to be fundamentally teration and phagocytic recognition) (Fig. 1). Initiation important in development also occurs in normal of apoptosis may occur following the binding of death physiological circumstances. Apoptotic vascular promoting factors (e.g. Tumour Necrosis Factor (TNF) smooth muscle cells (VSMCs) have been identified and Fas Ligand) to cell surface TNF and Fas death during the physiological regression and closure of receptors or by a withdrawal of survival factors (e.g.
the human ductus arteriosus before Similarly, reduced insulin-like growth factor, loss of cell–cell apoptotic VSMCs and endothelial cells are present in and cell–matrix contact) acting via the mitochondria.
umbilical veins and arteries following the significant Alternatively apoptosis may be initiated by ionising haemodynamic changes that occur during Such radiation or chemotherapeutic agents acting directly apoptosis appears to be triggered by a reduction in on DNA.
blood flow. Further support comes from experimental The control and execution stage of apoptosis is studies using immature rabbits which demonstrate dependent on the sequential activation of a group of that reducing flow in the common carotid artery, by cysteine proteases referred to as caspases. Activation ligating the external carotid, results in both VSMC and ofcaspase-8occursfollowingbindingofthecellsurface endothelial cell The normal blood vessel death-receptors (TNF and Caspase-9 is activated wall is characterised by a low endothelial cell turnover by cytochrome C released from mitochondria stim- with a variety of mechanisms affording protection ulated by the withdrawal of survival factors. Both against Indeed, recent data indicate that caspase-8 and 9 can activate the final executioner, apoptosis may be important in the pathophysiology caspase-3, which in turn causes the irreversible frag- of vascular disease. A better understanding of this mentation and degradation of DNA.
Control of the execution phase is achieved by anti- ∗ Please address all correspondence to: T. C. F. Sykes, Department apoptotic proteins belonging to the Bcl-2 family (Bcl- of Vascular Surgery, Research Institute, Lincoln House, Birmingham Heartlands Hospital, Birmingham B9 5SS, U.K.
2, Bcl-XL) inhibiting pro-apoptotic proteins (Bax and 1078–5884/01/110389+07 $35.00/0  2001 Harcourt Publishers Ltd.
T. C. F. Sykes et al.
Fig. 2. A schematic summary of pro-apoptotic and survival factors
typically affecting the endothelial cell. A loss of survival factors will also precipitate apoptosis. ROS (reactive oxygen species), VEGF (Vascular endothelial cell growth factor).
apoptosis in tissue sections. The major drawback of Fig 1. A schematic diagram illustrating four functional stages of
the TUNEL technique is that nuclei can be stained apoptosis and the three major pathways through which the cascade non-specifically due to differences in cell fixation and of cellular events can proceed. The three pivotal caspases (8, 9 also non-nuclear structures in atherosclerotic plaques and 3) are shown with caspase-3, the final executioner, causing irreversible DNA damage and loss of cell viability. Control is may be stained. It is recommended that this technique achieved with the regulatory pro and anti-apoptotic proteins (Bax/ be used in conjunction with an additional mor- Bid & Bcl2 respectively). TNF (Tumour necrosis factor/receptor), Fas L (Fas Ligand), Fas (Fas receptor), DD (TNF death domain protein), FADD (Fas-associated death domain), IGF (Insulin-like Additional methods, suitable for in vitro use only, growth factor) and PS (Phosphatidylserine).
phatidylserine (PS) residues, that occurs in early apo- Bid) that facilitate the release of cytochrome C from the ptosis, with a fluorescein (FITC) conjugate of Annexin- mitochondria. The relative amounts of these proteins V, a protein that has a high natural affinity for PS.
determines whether the cell undergoes apoptosis or This method allows quantitative assessment of apo- not. Structural and morphological changes to the cell ptotic cells either by fluorescence microscopy or flow occur following the internucleosomal fragmentation cytometry.
of DNA leading to an irreversible loss of cell viability.
Early apoptotic cells are characterised by ex- ternalisation of phosphatidylserine (PS) residues, Pro-apoptotic Factors Implicated in Vascular Cell
which are normally situated on the inner leaflet of the plasma membrane. This feature facilitates the specific recognition of apoptotic cells by macrophages enabling In vitro studies have shown that extracellular agents, their elimination by phagocytosis.
including well characterised cardiovascular risk fac- The efficient removal of apoptotic cells can make tors and inflammatory mediators induce apoptosis of their identification difficult. Historically the detection endothelial cells and vascular SMCs. (Fig. 2).
and quantification of apoptotic cells has relied on morphological assessment by electron microscopy or light Newer techniques rely on the de- tection of fragmented DNA by terminal transferase Oxidised Low Density Lipoprotein (OxLDL) mediated dUTP-biotin nick end labelling (TUNEL) or in situ nick translation Both methods have Elevated LDL is a significant risk factor for coronary become the standard technique for the detection of artery disease. Specifically, its oxidised form (OxLDL) Eur J Vasc Endovasc Surg Vol 22, November 2001

Apoptosis in Vascular Disease
is considered to play a key role in the development of premature atherosclerosis through the formation of foam cells and fatty OxLDL is known to be cytotoxic to cultured endothelial cells and has also been shown to induce apoptosis, in bovine aortic endothelial cells and human umbilical vein endothelial cells OxLDL-induced apoptosis is in- hibited by the addition of the antioxidant vitamins C and and is therefore believed to act through the generation of reactive oxygen species. Cultured vas- cular smooth muscle cells also undergo apoptosis when exposed to oxLDL and Fig. 3. Phase contrast microscopy of cultured human umbilical
venous endothelial cells (HUVECs). A: control cells with a char- acteristic cobblestone morphology, B: After 4 h incubation with homocysteine and adenosine (0.5 mM) showing contracted apoptotic Hyperglycaemia/advanced glycation end products Cytokines and inflammatory mediators Endothelial cells cultured with high concentrations of The inflammatory cytokines TNF!, IL-1" and IFN- glucose (30 mmol/L) for 48 h show increased apoptosis # have all been identified in human atherosclerotic compared with those incubated in low concentrations TNF! causes endothelial cell of glucose (5 High glucose also appears to through the activation of caspase-3 and may be in- induce apoptosis through the generation of hydrogen hibited by specific inhibitors of this In- peroxide and can be inhibited by antioxidants such terestingly, TNF! can also activate a survival pathway as ascorbic Similarly high concentrations of that requires protein Inhibitors of RNA advanced glycation end products, the products of non- transcription or protein synthesis can therefore aug- enzymatic glycation of proteins in the circulation, can ment TNF!-induced apoptosis of endothelial cells. In induce apoptosis of endothelial cells after 48 In- contrast TNF!, does not cause apoptosis of cultured terestingly, the lipid-lowering drug pravastatin can human smooth muscle cells on its own, but does so prevent hyperglycaemia induced which when combined with IL-1" and IFN-Lipo- contrasts with the proapoptotic effects of the lipophilic polysaccharide also induces human endothelial cell statins (atorvastatin, simvastatin and lovastatin) on apoptosis in vitro that can be prevented by anti- vascular smooth muscle This effect also occurs in vivo, but unlike the in vitro setting is dependent on TNF! Angiotensin II, although promoting growth of VSMCs, induces endothelial apoptosis in vitro in a dose de- Hyperhomocysteinaemia is, an independent risk factor for cardiovascular disease, and, is known to cause Reactive oxygen species endothelial We have recently shown that homocysteine in combination with adenosine, an Elevated reactive oxygen species (ROS) are an early important substrate in homocysteine metabolism, can hallmark of In vitro evidence indicates induce apoptosis of cultured HUVECs and human that ROS, the by-product of aerobic metabolism, in- duce endothelial and smooth muscle cell long saphenous vein endothelial cells after as little as 4 h (Fig. 3). These effects can be prevented ROS may be produced in the vessel wall by macro- by vitamin B6, B12 and cofactors in homo- phages within the atherosclerotic plaque or endo- cysteine metabolism and currently used as homo- genously by human endothelial and vascular smooth cysteine-lowering agents in clinical trials. The latter muscle cells. The proatherosclerotic and proapoptotic finding may represent an important mechanism by factors oxLDL, TNF!, glucose and angiotensin II, all which vitamin supplementation can reduce vascular induce endogenous ROS whose effects can be pre- injury associated with hyperhomocysteinaemia.
Eur J Vasc Endovasc Surg Vol 22, November 2001 T. C. F. Sykes et al.
Survival Factors Implicated in Preventing
Vascular Cell Apoptosis
The survival of endothelial cells and vascular smooth Shear stress and nitric oxide muscle cells is dependent on contact with adjacent cells and the extracellular matrix (Fig. 2). This is me- Cultured endothelial cells (HUVECs) undergo a basal diated by cellular adhesion molecules such as the level of apoptosis in the absence of flow, which can be integrins, which also function as signalling molecules.
inhibited by mimicking flow conditions in a perfusion Apoptosis occurs when these contacts are Under chamberLaminar flow generates shear stress at the normal circumstances the extracellular matrix gen- endothelial cell surface that can prevent apoptosis erates survival signals that either suppress apoptotic induced by different stimuli including TNF!, oxLDL pathways or lead to an increase in the activity of and ROS. This inhibition is mediated by shear stress- anti-apoptotic pathways such as the Bcl-2 family of induced release of nitric oxide (NO) that subsequently inactivates In the normal vasculature the shear stress associated with laminar flow causes a continuous production of NO by endothelial cells, providing protection from injury and apoptosis. How- Apoptosis and Vascular Disease
ever atherosclerotic plaque-prone areas are typically sites of turbulent blood flow and low shear stress, and are associated with increased cell which is most probably secondary to increased Early studies in cholesterol-fed swine have shown cell death to be a major component of atherosclerotic plaque In situ techniques (TUNEL) have since confirmed the presence of apoptotic smooth muscle cells, T-lymphocytes, and macrophages in Growth factors human atherosclerotic More recently Tricot et have examined carotid endarterectomy Cultured endothelial cells deprived of growth factor specimens and shown that apoptotic luminal endo- undergo Addition of vascular endothelial thelial cells occur with a greater prevalence in the growth factor (VEGF) can inhibit apoptosis induced post-stenotic area, a region of low flow and low shear by TNF!ionising and disruption of the stress.
extracellular Angiopoietin-1 can also prevent Apoptotic cell death within plaques, as determined apoptosis in growth factor deprived endothelial by the TUNEL technique, ranges from <2% to 30% and Basic fibroblast growth factor (FGF-2) prevents lipo- is related to the stage of the atherosclerotic popolysaccharide induced endothelial cell apoptosis in Very little apoptosis occurs in intimal thickening vivo and serum and growth factor deprivation induced and fatty streaks with the majority of apoptotic cells apoptosis in In cultured human vascular occurring in advanced atherosclerotic plaques within smooth muscle cells several growth factors (insulin- regions of macrophage like growth factor, platelet derived growth factor, basic Although the above evidence indicates that apo- fibroblast growth factor, and transforming growth fac- ptosis does occur within human atherosclerotic tor) inhibit apoptosis especially under low serum con- plaques, other authors have used electron microscopy to show that despite >10% TUNEL-positive nuclei, the vast majority of injured and disintegrating cells within plaques display typical features of cells undergoing Although the relative importance of cell death by apoptosis versus necrosis is unknown we can speculate Oestrogen is an established atheroprotective hormone, that apoptosis may allow plaque stabilisation. Apo- which is known to produce beneficial changes in lipid ptotic removal of T-cells and macrophages, which profile and the regulation of vascular tone. Oestradiol commonly infiltrate the shoulder region of the fibrous also maintains endothelial integrity by inhibiting endo- cap, would reduce matrix metalloproteinase (MMP) thelial apoptosis induced byTNF!Antioxidant vit- synthesis and extracellular matrix breakdown without amins C and E, especially in combination, prevent an accompanying inflammatory reaction. Conversely apoptosis induced by oxLDL, TNF!, and death of vascular smooth muscle cells in plaques, Eur J Vasc Endovasc Surg Vol 22, November 2001 Apoptosis in Vascular Disease
either through apoptosis or necrosis, may lead to a weakening of the fibrous cap as a consequence of reduced collagen and extracellular matrix synthesis Medial SMC loss prior to the development of occlusive following the loss of smooth muscle cells.
and intimal proliferative lesions is characteristically Apoptosis of luminal endothelial in athero- found in transplant arteriopathy. Experimental evi- sclerotic plaques may initiate plaque erosion with dence using rat arterial allografts suggest that this the subsequent promotion of platelet aggregation and SMC loss is due to Endothelial damage, thrombosis. Apoptotic vascular cells themselves may also seen in transplant arteriopathy, appears to be due also lead to increased plaque thrombogenicity. Both to a Fas-based apoptotic apoptotic smooth muscle cells and endothelial cells expose phosphatidylserine residues on their surface in early apoptosis, which in the presence of factor V and VII, can act as a substrate for the generation of Additionally apoptotic monocytic cells Apoptoticcellsarequicklyeliminatedbyneighbouring have enhanced tissue factor Mallat et phagocytic cells making in vivo identification difficult.
have also identified increased tissue factor expression Our current understanding of apoptosis in vascular around apoptotic cells within the central necrotic core disease therefore depends almost entirely upon in vitro of plaques, indicating that tissue factor is shed from and in situ data. However, recent techniques, which apoptotic cells via apoptotic microparticles.
capture shed microparticles released by apoptotic cells, have been used to show increased apoptosis in acute Induction of apoptosis Apoptosis of smooth muscle cells will occur following balloon injury in animal models. An initial apoptotic Atherosclerotic plaques in cholesterol-fed rabbits re- response after 30 is followed by persistent apo- gress when neointimal cell apoptosis is induced by ptosis after two weeks, the latter associated with the inhibiting the antiapoptotic protein Plaque re- regulation of intimal Studies of human gression also occurs following administration of L- restenotic plaques indicate there may be an increased arginine to induce macrophage apoptosis via NO re- apoptotic rate, but there is no consensus. Isner et Interestingly, Schaub et found that when found an increased apoptotic rate in human restenotic vascular smooth muscle cell apoptosis is induced, plaques, whereas Bauriedel et noted reduced levels through the overexpression of death domain proteins, of apoptotic cells in restenotic plaques compared with macrophages are recruited and neointimal progression primary plaques.
rather than regression occurs.
Various attempts to induce apoptosis have been tried in animal models of neointima formation and restenosis following angioplasty. Transfection of sui- cide genes into smooth muscle cells or direct delivery of pro-apoptotic ligands (Fas-ligand) into the vessel wall induce smooth muscle cell apoptosis and a sig- nificant reduction in neointima formation in rabbit Reduced smooth muscle cell density within the elastic arteries following Adopting this ap- media of human aneurysmal wall is associated with proach in the human clinical setting may however, increased smooth muscle cell Further risk the development of aneurysms.
evidence has shown that infiltrating T cells express cytotoxic mediators such as cytokines, perforin and Fas/Fas ligand, which are capable of inducing apo- ptosis. It is hypothesised that these might contribute Inhibition of apoptosis to the elimination of smooth muscle cells, a source of collagen and elastin, thereby impairing repair and Currently there is no information on the effect of maintenance of the arterial extracellular matrix tending inhibiting apoptosis on the progression or com- to favour aneurysmal wall expansion.
plications of vascular disease. In vitro and in situ data Eur J Vasc Endovasc Surg Vol 22, November 2001 T. C. F. Sykes et al.
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