Darwinian Medicine and Endothelial Dysfunction

8/13/2019 Darwinian Medicine and Endothelial Dysfunction

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arwinian MedicineWhat Evolutionary Medicine Offers

to ResearchersRandolph M. Nesse an d Alan Weder

The University of Michigan, Ann Arbor

Almost ll our detailed knowledge about theis proximate knowledge about its structure, development,and functioning, and how its dysfunctions lead to disease.The other, evolutionary half of endothelial biology has beenneglected. Some researchers are unfamiliar with the fun-damental distinction between proximate and evolutionaryquestions, and methods for formulating and testing evolu-tionary hypotheses about the remain underap-preciated. This chapter offers a brief overview ofthe distinctionbetween evolutionary and proximate explanations, followedby an introduction to evolutionary medicine and its applica-tions to the .

TWO SEP R TE BIOLOGIC L QUE STION SErnst Mayr passed away early in 2005 at age 100, shortly afterpublishing his twentieth book and the last of his 700 scien-tific articles. One of his enduring contributions was his doggedemphasis on the importance of distinguishing proximate fromevolutionary (sometimes called ultimate) biological explana-tions. His treatise, The Growth of Biological Thought, tracesthese 'two only-occasionally intersecting threads in biology:one that studies how things work (proximate), the other that

studies why organisms are the way they are (evolutionary)1). His final book, What Makes Biology Unique, continuesand updates the theme 2). Over and over again, he makes thepoint that every biological trait needs both a proximate expla-nation of its structure and operation, and an evolutionaryexplanation of why it is the way it is. For example, an expla-nation of the structure of chlorophyll and how it capturesphotons and traps their energy in chemical bonds is essential.Equally important, however, is an evolutionary explanationof the biological history of chlorophyll and how its particularform gives a selective advantage. As many will know, the storyis intriguing, with the machinery for photosynthesis evolvingin one-celled organisms about 3.5 billion years ago, probablyin the precursors to cyanobacteria. It has been only about 1 bil-lion years, however, since those organisms were incorporatedinto the eukaryotic cell as chloroplasts. A complete biologicalexplanation of chlorophyllneeds both a proximate descriptionof how chloroplasts work, and an evolutionary explanation ofthe selection forces and phylogenetic pathways that gave themtheir current characteristics, nstead of others.The distinction between how and why questions wasdeveloped further by Tinbergen, in a seminal article describinghis famous Four Questions (3). Here, he divides proximatequestions into two subtypes: those about the structure of atrait and those about its ontogeny. He also divides evolution-ary questions into those about how a trait gives a selectiveadvantage and those about the phylogeny of a trait. Implicit inthis classification is the need to address four separate questionswhen offering a full biological explanation for any trait. lltoo often, the four questions are inadequately distinguishedor incorrectly taken to be alternatives. Sometimes the evo-lutionary questions are not taken seriously or are ignoredcompletely.Much of this situation is understandable because edu-cation about these aspects of evolutionary biology often is

arwinian MedicineWhat Evolutionary Medicine Offers

to Endothelium ResearchersRandolph M. Nesse an d Alan Weder

The University of Michigan, Ann Arbor

Almost ll our detailed knowledge about the endotheliumis proximate knowledge about its structure, development,and functioning, and how its dysfunctions lead to disease.The other, evolutionary half of endothelial biology has beenneglected. Some researchers are unfamiliar with the fun-damental distinction between proximate and evolutionaryquestions, and methods for formulating and testing evolu-tionary hypotheses about the endothelium remain underap-preciated. This chapter offers a brief overview ofthe distinctionbetween evolutionary and proximate explanations, followedby an introduction to evolutionary medicine and its applica-tions to the endothelium.

TWO SEP R TE BIOLOGIC L QUE STION SErnst Mayr passed away early in 2005 at age 100, shortly afterpublishing his twentieth book and the last of his 700 scien-tific articles. One of his enduring contributions was his doggedemphasis on the importance of distinguishing proximate fromevolutionary (sometimes called ultimate) biological explana-tions. His treatise, The Growth of Biological Thought, tracesthese 'two only-occasionally intersecting threads in biology:one that studies how things work (proximate), the other that

studies why organisms are the way they are (evolutionary)1). His final book, What Makes Biology Unique, continuesand updates the theme 2). Over and over again, he makes thepoint that every biological trait needs both a proximate expla-nation of its structure and operation, and an evolutionaryexplanation of why it is the way it is. For example, an expla-nation of the structure of chlorophyll and how it capturesphotons and traps their energy in chemical bonds is essential.Equally important, however, is an evolutionary explanationof the biological history of chlorophyll and how its particularform gives a selective advantage. As many will know, the storyis intriguing, with the machinery for photosynthesis evolvingin one-celled organisms about 3.5 billion years ago, probablyin the precursors to cyanobacteria. It has been only about 1 bil-lion years, however, since those organisms were incorporatedinto the eukaryotic cell as chloroplasts. A complete biologicalexplanation of chlorophyllneeds both a proximate descriptionof how chloroplasts work, and an evolutionary explanation ofthe selection forces and phylogenetic pathways that gave themtheir current characteristics, nstead of others.The distinction between how and why questions wasdeveloped further by Tinbergen, in a seminal article describinghis famous Four Questions (3). Here, he divides proximatequestions into two subtypes: those about the structure of atrait and those about its ontogeny. He also divides evolution-ary questions into those about how a trait gives a selectiveadvantage and those about the phylogeny of a trait. Implicit inthis classification is the need to address four separate questionswhen offering a full biological explanation for any trait. lltoo often, the four questions are inadequately distinguishedor incorrectly taken to be alternatives. Sometimes the evo-lutionary questions are not taken seriously or are ignoredcompletely.Much of this situation is understandable because edu-cation about these aspects of evolutionary biology often is

Evolutionary, or Darwinian, medicine simply brings the

power of evolutionary biology to bear on the problems ofmedicine. Some areas, such as pathogen evolution and pop-

ulation genetics, are well developed. Another aspect, empha-

sized in medicine, is the enterprise of formulating

and testing hypotheses about why natural selection has not

shaped bodies that are more resistant to disease. The six key

reasons for traits that leave bodies vulnerable to disease are

reviewed below. Each is illustrated with examples from gen-

eral medicine, and then with examples from a major disease

of the endothelium, atherosclerosis.


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Defenses Are Useful Despite Their CostsFinally, there exist the body's many protective responses suchas pain, fever, vomiting, cough, and inflammation. Althoughthey cause suffering and often bodily damage, they are use-ful responses, not defects. Their costs are trade-offs for thebenefits they offer. It is all too easy to imagine that defensesare problems. For instance, the fever, pain, fatigue, and coughthat accompany a cold do not seem to be obviously useful.This clinician's illusion that they are problems is bolsteredbecause blocking them with drugs seems to cause few compli-cations. However, this is only because the body has so manyredundant defense systems, and because the systems that reg-ulate defense expression are shaped to express defenses when-ever that is worthwhile. If there is any uncertainty in when toexpress them, this means a normal system will have many falsealarms. Many defenses, such as vomiting or panicked flight, arequite inexpensive compared to the huge costofnot respondingto a real danger such as intestinal infection or an approachingtiger. The defense should be expressed whenever the averagebenefit is greater than the average cost, so many false alarmsare normal and to be expected. This has been called TheSmoke Detector Principle, because we tolerate false alarmsfrom burnt toast to ensure that the alarm sounds every sin-gle time even a small fire occurs (19). Disrupting defenses isnot, however, completely benign; using drugs to block fever,cough, or diarrhea can lead to serious consequences (6).

EVOLUTIONARY ANALYSIS OF ENDOTHELIALDYSFUNCTION AND ATHEROSCLEROSISThe healthy contributes to several processesof obvious adaptive advantage: control of hemostasis, pro-tection of subendothelial structures from circulating blood,local modulation of hemodynamics, and defense againstinfection. Endothelial dysfunction, broadly defined, can belethal, as evidenced by von Wiebrand disease and endo-toxic shock. Subtler endothelial dysfunction is characteristicof early atherosclerosis, an important disease of the developedworld. Although we cannot know for certain, it is unlikely thatatherosclerosis caused significant morbidity or mortality inthe pre-agricultural era, and indeed modern hunter-gatherersare little affected by atherosclerosis (see Chapter 16). How-ever, atherosclerosis is now epidemic in developed societiesworldwide, suggesting a near universal predisposition for thedisease, with some of the variation in vulnerability arisingfrom genetic differences. Although some common vulnera-bility factors, such as low levels of high-density lipoprotein(HDL) cholesterol, may result from the accumulation of mul-tiple rare alleles in a specific population, most probably theyresult from common allelic variants found in all populations(20). The apolipoprotein E story is particularly germane inthis regard 21). Common and widely dispersed genetic pat-terns are of ancient origin, and thus presumably predisposeall humans to disease susceptibility when they interact with

modern conditions. Indeed, even in recent historical times,transitions from relatively low to high rates of atheroscle-rosis have been observed to accompany cultural transi-tions.At this early juncture, it is important to acknowledgeexplicitly that we do not propose that genes for atherosclero-sis exist. Rather, we believe that those suites of genes, sharedby most of us, that now exact a net cost were preserved becausethey have yielded a net benefit over evolutionary time. Thismay be because dietary changes interact with these genes toimpose costs throughout life, or because the benefits dur-ing early life are larger for some genes than are their adverseconsequences during adulthood antagonisticpleiotropy).Themassive amount of work constituting the bulk of the currentvolume provides insights about the proximate mechanismsby which atherosclerosis arises and progresses, and we drawheavily on that mechanistic knowledge. Our task is to suggestreasons why natural selection over the past hundred thousandyears conserved an essentially universal vulnerability to suchan important disease process.Although early atherosclerosis usually is characterized asendothelial dysfunction, and the progression of atheroscle-rosis as a response to injury, close examination ofearly eventsshows the to be functioning in a largely normalmanner, at least as regards one of its primary functionsimmunity. For most of hominid history, infections have rep-resented grave threats, whether arising from injury, peripar-tum infection, or endemic pathogens. The nature, althoughnot the risk, of infectious disease changed as settled com-munities developed (11). Increased population density per-mitted human-to-human disease transmission, leading to therise of epidemic disease, and animal domestication led to theemergence of novel zoonoses, especially evident now as avianinfluenza threatens. Innate and acquired immunological func-

tions that eliminate or suppress infections are highly conservedas powerful and often apparently redundant defenses. The evo-lution of such systems cannot reasonably be attributed to any-thing other than incremental beneficial genetic changes thatimproved the reproductive success of those individuals whohad them. The contributes very importantly toimmunity, and one of its functions the controlled trans-port of intravascular substances and cells to the subendothe-lial space seems to predispose us to atherosclerosis. Althoughthis could be interpreted as a simple defect, it appears muchmore like an adaptation that has benefits that are equal to orgreater than its costs in a classic trade-off.Atherosclerotic lesions begin as low-density lipoprotein(LDL) particles accumulate in the subintimal space (22). Theconcentration of LDL in the blood is an important deter-minant of the rate of accumulation, as is the concentra-tion of HDL available for reverse cholesterol transport outof the tissue. However, the trafficking of lipoproteins acrossthe is not passive. Rather, LDL and HDL crossendothelial cells (ECs) by means of pinocytosis, which allowsthe delivery oftriglycerides and cholesterol for metabolic sup-port, cell growth, and steroidogenesis.


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E N D O T H E L I L I OMED I C I NE

Defenses Are Useful Despite Their CostsFinally, there exist the body's many protective responses suchas pain, fever, vomiting, cough, and inflammation. Althoughthey cause suffering and often bodily damage, they are use-ful responses, not defects. Their costs are trade-offs for thebenefits they offer. It is all too easy to imagine that defensesare problems. For instance, the fever, pain, fatigue, and coughthat accompany a cold do not seem to be obviously useful.This clinician's illusion that they are problems is bolsteredbecause blocking them with drugs seems to cause few compli-cations. However, this is only because the body has so manyredundant defense systems, and because the systems that reg-ulate defense expression are shaped to express defenses when-ever that is worthwhile. If there is any uncertainty in when toexpress them, this means a normal system will have many falsealarms. Many defenses, such as vomiting or panicked flight, arequite inexpensive compared to the huge cost of not respondingto a real danger such as intestinal infection or an approachingtiger. The defense should be expressed whenever the averagebenefit is greater than the average cost, so many false alarmsare normal and to be expected. This has been called TheSmoke Detector Principle, because we tolerate false alarmsfrom burnt toast to ensure that the alarm sounds every sin-gle time even a small fire occurs (19). Disrupting defenses isnot, however, completely benign; using drugs to block fever,cough, or diarrhea can lead to serious consequences (6).

EVOLUTION RY N LYSIS OF ENDOTH ELI LDYSFUN CTION ND THEROSCLEROSIS

The healthy contributes to several processesof obvious adaptive advantage: control of hemostasis, pro-tection of subendothelial structures from circulating blood,local modulation of hemodynamics, and defense againstinfection. Endothelial dysfunction, broadly defined, can belethal, as evidenced by von Willebrand disease and endo-toxic shock. Subtler endothelial dysfunction is characteristicof early atherosclerosis,an important disease of the developedworld. Although we cannot know for certain, it is unlikely thatatherosclerosis caused significant morbidity or mortality inthe pre-agricultural era, and indeed modern hunter-gatherersare little affected by atherosclerosis (see Chapter 16). How-ever, atherosclerosis is now epidemic in developed societiesworldwide, suggesting a near universal predisposition for thedisease, with some of the variation in vulnerability arisingfrom genetic differences. Although some common vulnera-bility factors, such as low levels of high-density lipoprotein(HDL) cholesterol, may result from the accumulation of mul-tiple rare alleles in a specific population, most probably theyresult from common allelic variants found in all populations(20). The apolipoprotein E story is particularly germane inthis regard (21). Common and widely dispersed genetic pat-terns are of ancient origin, and thus presumably predisposeall humans to disease susceptibility when they interact with

modern conditions. Indeed, even in recent historical times,transitions from relatively low to high rates of atheroscle-rosis have been observed to accompany cultural transi-tions.At this early juncture, it is important to acknowledgeexplicitly that we do not propose that genes for atherosclero-sis exist. Rather, we believe that those suites of genes, sharedby most of us, that now exact a net cost were preserved becausethey have yielded a net benefit over evolutionary time. Thismay be because dietary changes interact with these genes toimpose costs throughout life, or because the benefits dur-ing early life are larger for some genes than are their adverseconsequences during adulthood antagonisticpleiotropy).Themassive amount of work constituting the bulk of the currentvolume provides insights about the proximate mechanismsby which atherosclerosis arises and progresses, and we drawheavily on that mechanistic knowledge. Our task is to suggestreasons why natural selection over the past hundred thousandyears conserved an essentially universal vulnerability to suchan important disease process.Although early atherosclerosis usually is characterized asendothelial dysfunction, and the progression of atheroscle-rosis as a response to injury, close examination ofearly eventsshows the to be functioning in a largely normalmanner, at least as regards one of its primary functionsimmunity. For most of hominid history, infections have rep-resented grave threats, whether arising from injury, peripar-tum infection, or endemic pathogens. The nature, althoughnot the risk, of infectious disease changed as settled com-munities developed (11). Increased population density per-mitted human-to-human disease transmission, leading to therise of epidemic disease, and animal domestication led to theemergence of novel zoonoses, especially evident now as avianinfluenza threatens. Innate and acquired immunological func-

tions that eliminate or suppress infections are highly conservedas powerful and often apparently redundant defenses. The evo-lution of such systems cannot reasonably be attributed to any-thing other than incremental beneficial genetic changes thatimproved the reproductive success of those individuals whohad them. The contributes very importantly toimmunity, and one of its functions he controlled trans-port of intravascular substances and cells to the subendothe-lid space eems to predispose us to atherosclerosis. Althoughthis could be interpreted as a simple defect, it appears muchmore like an adaptation that has benefits that are equal to orgreater than its costs in a classic trade-off.Atherosclerotic lesions begin as low-density lipoprotein(LDL) particles accumulate in the subintimal space (22). Theconcentration of LDL in the blood is an important deter-minant of the rate of accumulation, as is the concentra-tion of HDL available for reverse cholesterol transport outof the tissue. However, the trafficking of lipoproteins acrossthe is not passive. Rather, LDL and HDL crossendothelial cells (ECs) by means of pinocytosis, which allowsthe delivery of triglycerides and cholesterol for metabolic sup-port, cell growth, and steroidogenesis.


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The macrophage is another key player in atheroscle-rosis (22,23). Although macrophages normally resident inthe subintima can handle some foreign antigens, the localresponse to tissue infection triggers an elaborate signalingsystem marshalling a defense reaction that includes the trans-endothelial migration of large numbers ofmonocytes and sub-sequent differentiation into macrophages to engulf bacteriaand expose them to lysosomal enzymes. Macrophage phago-cytosis and the intracellular lysosomal degradation of bacte-ria are efficient, but via coevolution, some organisms havederived strategies to frustrate macrophage capabilities. Thus,although bacteria that can be opsonized are cleared efficiently,many bacteria (e.g., Listeria and tuberculosis) have evolvedresistance to the constitutive killing mechanisms used bymacrophages such that they can survive, even intracellularly.Chlamydia pneumoniaemay be of particular importance 24).The process of the development of bacterial resistance isreminiscent of how LDL particles take up residence in thesub , escape macrophage metabolism, and causedisease. Native LDL particles attach to macrophage LDL recep-tors and are efficiently engulfed and metabolized, just as bac-teria are. As part of this normal process, macrophage LDLreceptors are down regulated and, in consequence, individ-ual macrophages do not become overloaded with LDL parti-cles. However, under oxidizing conditions, LDL particles aretransformed to oxidized LDL particles that are taken up bymacrophages via alternative high-capacity scavenger recep-tors (CD36 and type A scavenger receptor [SR-A]) normallyemployed for the ingestion of bacteria. These receptors arenot down-regulated by the accumulation of oxidized LDL;macrophages continue to accumulate lipoprotein moieties ina relatively unregulated manner, leading to the cellular con-gestion evident in foam cells (22). Note, however, that duringthe early stages, both ECs and macrophages are doing whatthey are well adapted to do: that is, prevent invasion by micro-scopic threats. It is probably only in our modern environmentthat these processes are corrupted by excess lipoprotein levelsand oxidative stress that leads to disease.While macrophage functions are being subverted, theoverlying the early atherosclerotic esion is intactand functional. Indeed, it appears that the normal vessel isable to heal the early effects of subintimal foam cell accumula-tion. Fetuses show foam cell lesions, termed fatty streaks,during early development, particularly in hyperlipidemicmothers in which the fetal blood cholesterol level correlatesclosely with that of the mother (25). These early fatty streaksappear to regress later in pregnancy either as fetal choles-terol demand decreases or fetal production increases; fetalcholesterol requirements become less dependent on maternalsources, and fetal blood cholesterol concentration is no longercorrelated with that of the mother. The initial accumulationprobably reflects an example of fetal-maternal conflict: Therapidly developing fetus requires more cholesterol than it cansynthesize and is dependent on transplacental delivery, thuscreating a potential conflict with the mother who could usethese caloric resources for herself or a subsequent offspring.

M E D I C I N E

David Haig has pioneered this line of thought 26), as exem-plified in his chapter in this volume on such conflicts andtheir role in preeclampsia (Chapter 17). The consequences ofpoor fetal lipoprotein access are profound: Cholesterol defi-ciencies in the mother can cause severe fetal developmentaldefects, particularly in the lipid-rich brain. Not all the vascu-lar changes in the fetus may be reversible, however, becausepostnatal atherogenesis may be accelerated in the offspringof hypercholesterolemic mothers who develop hypercholes-terolemia themselves (27).In part, the healing process itself may induce atherosclero-sis. Lipoprotein(a) is an LDL-like particle with putative rolesin tissue repair and inhibition of fibrinolysis hat may also actas a surrogate for vitamin C in animals that have lost the abilityto synthesize the vitamin de novo. Lipoprotein(a) is limitedto a subgroup of primates (and interestingly appears to haveevolved independently in the hedgehog) in which it may haveevolved when injuries resulted from trauma and infection.When expressed in a modern milieu, in which endothelialdysfunction is widespread (27), the actions of lipoprotein(a)promote atherosclerosis. In fact, just as for macrophages andthe , lipoprotein(a) is doing what it does besttrying to heal injury.The aspects of the modern environment predisposing toatherosclerosis n the developed world are well known: dietaryexcess, sedentary lifestyle, cigarette smoking, air pollution,and diabetes, in addition to the acquired lipoprotein disor-ders of high LDL and low HDL concentrations. Although itis clear that the nonlipid risk factors can result in endothe-lial dysfunction, as evidenced by diminution of flow-mediateddilatation or responses to infused acetylcholine, it appears thatatherosclerosis develops only in the face of the lipid disor-ders. The key player is almost certainly LDL solated lowHDL-cholesterol or high blood pressure in knockout micewithout LDL are incapable of causing atherosclerosis; highLDL cholesterol seems to be the sine qua non of atheroscle-rosis. However, native LDL-cholesterol itself does not appearto be sufficient for triggering atherosclerosis; there appears tobe a requirement for oxidation. As noted above, LDL oxida-tion seems to be a key feature of the macrophage's inabilityto regulate LDL particle uptake, and oxidation likewise playsan important role in the progression of lesions by stimulatingsubintimal lipoprotein retention, cytokine elaboration, andthe chemoattraction of participating inflammatory cells bymacrophages. Oxidized LDL uptake is one of the factors pro-moting the release of inflammatory mediators. The inflam-matory response decreases nitric oxide (NO) production andcontributes to endothelial dysfunction (by which is meantthe vasodilator response to NO-mediated agonists) 28).Macrophage responses may not be confined to vessels, asrecently suggested by observations of macrophage infiltrationinto adipose tissue, where elaboration of cytokines also occurs.Lerke and Lazar (29) have recently suggested the possibilitythat fat cells are recognized as invaders by macrophages, trig-gering responses similar to those causing atherosclerosis. If so,the sequence would add credence to the idea that macrophage


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activity and its attendant ill effects on the are con-served evolutionary responses of broad utility that are ren-dered harmful by modern environments. Although many as-pects of the environment contribute to atherosclerosis, ll seemto operate through LDL oxidation which, in a sense, serves toprotect LDL particles from intracellular metabolism and, inthat way, mimics one of the strategies followed by bacteria.

Returning to the question of why this most useful processhas come to cause atherosclerosis, the most obvious factoris the level and kinds of lipids characteristic in contempo-rary human diets. Hunter-gather and traditional rural soci-eties have serum cholesterol evels far below those of Western-ized populations. Indeed, less than 5 of adults in the UnitedStates have a total cholesterol ofless than 150mg/dL, the aver-age value in the more biologically normal populations (30).Thus, in essence, almost everyone in the United States, and inmany other Westernized countries, is hypercholesterolemic,and the situation for triglycerides is similar. Undoubtedly, oursocietal hyperlipidemias are overwhelminglydue to diet, bothits macronutrient composition and its caloric excess, particu-larly when such a diet is coupled with a sedentary lifestyle. Theeffect of modern lifestyle is Syndrome X which in additionto promoting hyperlipidemia also increases oxidative stress,resulting in increased levels of atherogenic oxidized LDL (31).One way of thinking about atherosclerosis is to view it asthe result of an evolved adaptive response that protects againstinfection but that results in endothelial injury in modern envi-ronments. Because the consequences of the injury occur latein life, natural selection preserves those systems promotingatherosclerosis n preference to those suppressing them, a clas-sic case of antagonistic pleiotropy. This is a trade-off, but notquite a classic one. Because the costs were probably minimaluntil the past century, and because they caused no harm untilmodern times, the genetic variations that increase vulnerabil-ity to atherosclerosis are not really defects, but are insteadexcellent examples of genetic quirks that give rise to unto-ward effects only when they interact with factors encounteredin modern environments. These speculations about the adap-tive roots of atherosclerosisgive rise to a specificprediction thatindividuals who have a genetic predisposition to atheroscle-rosis may be less vulnerable to infection and more susceptibleto other inflammatory diseases. In regards to the questionof autoimmune diseases, data demonstrate a strong associa-tion between rheumatoid arthritis and accelerated atheroscle-rosis (32), although the authors of that article suggest thatthe chronic low-grade inflammation of arthritis activates theatherosclerotic process rather than vice versa. In truth, the rela-tionship may be bidirectional, with each process reinforcingthe other.The adaptive significance of the systems that leave us vulnerable to atherosclerosis is only one half of a full evolu-tionary explanation. We also need to know the phylogenyof those systems, and particularly if path dependence hasconstrained them so that natural selection cannot shape aless vulnerable mechanism. Although it would conceivably bepossible to develop alternative ways of preserving the func-

tions of lipoproteins necessary for blood-borne triglycerideand cholesterol delivery while preventing excessive pinocy-totic delivery to subendothelial spaces, such an adaptationwould probably seriously compromise cholesterol-dependentcellular and immune processes. Because immune functionhas such obvious selective value whereas atheroscleroticdisease, primarily manifest late in life, presumably is not amajor selection force here would seem to be little tendencyto shape such an adaptation. However, too much of a goodthing is dangerous, as illustrated by chronic inflammatorydiseases such as rheumatoid arthritis accelerating atheroscle-rosis. Conversely, in situations in which 'innate immunity iscompromised (e.g., by inactivating mutations of the Toll-likereceptor 4 (TLR4) receptor, a pattern recognition receptorinvolved in lipopolysaccharide clearance), atherosclerosis isdecreased (33). Thus, in the trade-off of immune function ver-sus atherosclerosis, the benefits of immunity provide greateradvantages early in life when selection is stronger, thus leav-ing us with a strong predisposition to atherosclerosis.A signaldetection analysis of the costs and benefits of various regula-tory settings could further illuminate the situation (19).Are other evolutionary factors at work?A direct infectioushypothesis has been championed by Ewald, who contends thatatherosclerosis is triggered by infections that have coevolvedwith humans (24). Ofparticular interest has been the relation-ship of Chlamydia pneumoniae, an organism capable of livinginside inflammatory cells in blood vessel plaques. Ewald sug-gests that the bacterial infection, rather than being a bystandercolonizing a disrupted vascular wall, is pathogenetic. He fur-ther notes that in the case of inflammatory arthritis, a higherincidence of joint-fluid C. pneumoniae infections are associ-ated with a higher prevalence of the apolipoprotein ~4 geno-type. Because this is a risk factor for coronary disease, it ispossible the mechanism mediating risk is an increased suscep-tibility to C.pneumoniaeinfection and vascular inflammation.Clearly, if true, the early lesions could attract macrophages,increase local oxidative activity and, in the presence of LDLparticles, trigger atherosclerosis. n attempt at testing thishypothesis by treating patients with established atheroscle-rosis with antibiotics was negative (34), but. it is still plausi-ble to assume that the role of the bacterium is prominent inthe early disease but not after atherosclerosis has progressed.C. pneumoniae is not the only infection thought to accelerateatherosclerosis: Many chronic subclinical nfections, ncludingperiodontitis, sinusitis, bronchitis, and diverticulitis n factany source of chronic endotoxemia may provoke an inflam-matory response and increase the risk of atherosclerosis (35).The other major player in the atherosclerotic picture, HDL,may be a defense against atherosclerosis-promoting infectiousagents by acting as a scavenger of lipopolysaccharide (36).

ON LUSION

The implications of an evolutionary view of the endothe-lium are several. First and most obviously, in the absence of


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profound changes in the environment or human nature, itis unlikely that atherosclerosis can be prevented in the gen-eral population through the public health measures known tobe effective diet and exercise although they can be effec-tive for those individuals capable of modifying their behavior37). The burgeoning epidemic of obesity suggests that thelifestyle causing hyperlipidemia is triumphing to the extent

I that reducing cholesterol values to those of hunter-gatherersby lifestyle interventions is simply unrealistic. As a society,we seem to be much more willing, even eager, to embraceantiatherosclerotic strategies that depend on the administra-tion of costly drugs to already-ill individuals nearing the endof the natural history of atherosclerotic diseases. Given cur-rent costs, inequalities in health care delivery, and the poorpublic health infrastructure, such treatments, unfortunately,cannot reasonably be provided for population-wide treatmentand, in any case, they are not that effective. More promis-ing preventive approaches include modifications like statinsand antioxidants, although one line of argument developedabove suggests the need to be on guard for the possibilitythat antioxidants may increase other vulnerabilities. Epidemi-ological evidence supporting the benefits of dietary antiox-idants is encouraging, although the effectiveness of antiox-idants in intervention trials has been disappointing (23).Trials in established atherosclerosis may, however, be a caseof too little, too late, as atherogenesis is already well advanced,perhaps beyond the period in which antioxidants could beeffective. What is clear is that only with the development ofeffective preventive approaches that can be widely appliedwill any progress be made in preventing the complications ofatherosclerosis.One potentially beneficial feature of modern society isfound in Barker's hypothesis, which implies that improvedmaternal nutrition may decrease the development of featuresdescribed as the thrifty phenotype a set of metabolicadjustments programmed to promote calorie retention butwhich increase the risk of late-life atherosclerosis (38,39).Unfortunately, to realize the benefits of improved maternalnutrition, the environment of the offspring throughout lifewould have to promote avoidance of calories and fat excess,which again seems impracticable.Genetic engineeringhas been held out as a possible cure foratherosclerosis. We believe the evidence is overwhelming hatonly a small min the focus on gene hunting for atheroscle-rosis should therefore be on finding common allelic variantsor haplotypes controlling normal homeostatic functions.This is not to say that elucidation of monogenic diseases willnot lead to a better understanding of the vulnerabilities ofatherosclerotic disease progression, just as a molecular under-standing of the LDL receptor in familial hypercholesterolemiacontributed so importantly to the development of drugs usefulin preventing further progression of atherosclerosis.The iden-tification of the Milano Apo A mutation (40), which exerts apowerful protective effect against atherosclerosis by markedlyenhancing reverse cholesterol transport and presumably act-ing to heal the early atherosclerotic lesions before the sequence

of reinforcing mechanisms is recruited, may be another exarn-ple of how a monogenic disease can inform the developmentof prevention strategies.Just as genetic determinants are likely to be normal alle-les, normal immune processes predispose to atherogenesis.Could atherosclerosis be prevented by the selective modula-tion of immune function, specifically the physiological func-tions of macrophages involved in atherogenesis?Similarly,per-haps endothelial transport of LDL molecules can be targeted.The has its own protective mechanisms againstthe transport of larger lipoproteins such as very-low den-sity lipoprotein (VLDL). Perhaps a vaccination that slowedLDL-cholesterol transport could have promise for slowingatherosclerosis.Ceruloplasmin s a potential source ofoxidizedLDL (41); perhaps the copper-depleting drug developed forthe treatment of Wilson's disease of the liver, trientine, couldpossibly have an antiatheroscleroticeffect. Such speculationsdemonstrate the heuristic value of an evolutionaryperspectiveon the . We anticipate that readers of this volumewill bring a mass of sophisticated knowledge about the prox-imate mechanism involved in endothelial diseases. We hopethat this chapter will encourage some of them to ask new evo-lutionary questions about why the is the way it is,and why it leaves us so vulnerable to such common and devas-tating diseases. If they do, progress in endothelial biomedicinewill occur even faster.

REFERENCES

1 Mayr E. The Growth of Biological Thought: Diversity Evolutionand Inheritance. Cambridge: The Beknap Press of Harvard Uni-versity Press, 1982


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6 Nesse RM, Williams GC. Wh y We Get Sick. New York: TimesBooks, 1994.7 Stearns S, ed. Evolution in Health and Disease. Oxford: OxfordUniversity Press, 1998.8 Williams GC, Nesse RM. The daw n of Darwinian medicine.QRev Biol. 1991;66:1-22.9 Nee1 JV, Julius S, Wed er A, Yamada M , Kardia SL, Haviland MB.Syndrome X: is it for real? Gen Epidemiol. 1998;15:19.10 Eaton SB, Strassman BI, Nesse RM, et al. Evolutionary healthpromotion. Prev Med. 2002;34(2):109-118.11 Ewald P. Evolution of Infectious Disease. New York: Oxford Uni-versity Press, 1994.12 Williams GC. Th e Pony Fish s Glow: And Other Clues to Plan an dPurpose in Nature. New York: BasicBooks, 1997.

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￼Darwinian Medicine and Endothelial Dysfunction

Darwinian Medicine and Endothelial Dysfunction