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Endothelial Dysfunction and Essential Hypertension
  JOHTN
ENDOTHELIAL PATHOPHYSIOLOGY
Endothelial Dysfunction and Essential Hypertension
1Jay Khambhati, 2Suegene K Lee, 3Bryan Kindya, 4Devinder Dhindsa, 5Pratik B Sandesara, 6Arshed A Quyyumi
1-6Consultant
1-66Division of Cardiology, Department of Medicine, Emory ClinicalCardiovascular Research Institute, Emory University School ofMedicine, Atlanta, Georgia, USA
Correspondence Author: Suegene Lee, Consultant, Divisionof Cardiology, Department of Medicine, Emory ClinicalCardiovascular Research Institute, Emory University School ofMedicine, Atlanta, Georgia, US
e-mail: suegene.lee@emory.edu
 
ABSTRACT
Systemic hypertension is a chronic disorder of cardiovascularsystem characterized by an increase in systemic vascularresistance (SVR). Although the level of blood pressure is aproduct of SVR and cardiac output, it is the former which isresponsible for chronic blood pressure elevation. A number ofbiochemical, biophysical, and neuro-humoral factors participatein the maintenance of SVR. Whatever the underlying molecularmechanism may be for elevated SVR, the end consequenceis endothelial dysfunction. Normal endothelium promotesvasodilation and prevention of local thrombotic phenomenawhereas abnormal endothelium promotes vasoconstrictionand thrombotic processes. One of the basic pathophysiologicalaberrations in hypertension is abnormal endothelial function.A number of blood pressure lowering strategies (life-stylemodification and or anti-hypertensive drugs) result in reversingendothelial dysfunction in hypertension. Thus, endothelialfunction is considered both as a mechanism and a therapeutictarget in hypertension. This review summarizes the physiologyand pathophysiology of endothelium in hypertension.
Keywords: Aminothiols, Cardiovascular, Dimethylarginine,Hypertension.
How to cite this article: Khambhati J, Lee SK, Kindya B,Dhindsa D, Sandesara PB, Quyyumi AA. Endothelial Dysfunctionand Essential Hypertension. Hypertens J 2017;3(2):81-88.
Source of support: AAQ is supported by the National Institutesof Health (NIH) grants 5P01HL101398-02, 1P20HL113451-01,1R56HL126558-01, 1RF1AG051633-01, R01 NS064162-01, R01 HL89650-01, HL095479-01, 1U10HL110302-01,1DP3DK094346-01, 2P01HL086773-06A1.
Conflict of interest: None
 
 

INTRODUCTION

Endothelial cells form the innermost monolayer of thevascular wall in arteries, veins, and capillaries. Theendothelium functions both as an endocrine organ,expressing receptors for cellular and hormonal communication,and as a paracrine organ, producing vasoactive,inflammatory, vasculoprotective, angiogenic, thrombotic, and antithrombotic molecules.1,2 It exists in persistenthomeostasis, balancing blood fluidity and thrombosis,vascular inflammation and immunologic processes, andimportantly, regulating vascular tone. We will focus onendothelial regulation of vascular tone in hypertensionin this review.

Vascular tone is critically regulated by the endotheliumvia the synthesis and release of a variety of endotheliumderivedfactors that exist in a delicate balance with eachother. Endothelin-1 (ET-1), angiotensin II, thromboxaneA2, and reactive oxygen species mediate vasoconstriction,whereas nitric oxide (NO), prostacyclin, carbon monoxide,and other endothelium-derived hyperpolarizing factorsmediate vasodilation.3,4 Among these, NO appears to bea critical regulator of vascular homeostasis.5

 
PATHOPHYSIOLOGY OF ENDOTHELIAL
DYSFUNCTION AND HYPERTENSION


Endothelial dysfunction (ED) occurs early after the diagnosisof essential hypertension and may even precedeit.6 A major characteristic of ED is decreased NO bioavailability.Endothelial cells synthesize NO throughthe constitutive expression of nitric oxide synthase-3(NOS-3), also known as endothelial nitric oxide synthase(eNOS),6 which facilitates both coupled and uncoupledreactions. In the healthy endothelium, a coupled eNOSleads to a Ca2+/calmodulin (CaM)-dependent phosphorylationthat converts L-arginine to L-citrulline, resultingin generation of NO.1 The release of NO leads to smoothmuscle vasodilation via a cyclic guanylate monophosphate(cGMP)-mediated activation of guanylate cyclase,altering resting vasomotor tone.

In conditions of increased oxidative stress (OS), anuncoupled Ca2+/CaM-independent reaction generatessuperoxide anions rather than NO.1 In this state, Larginineand tetrahydrobiopterin (BH4) are depleted andperoxynitrite and asymmetric dimethylarginine (ADMA)levels are increased. Excess superoxide typically leads tofurther depletion of NO by formation of peroxynitrite,destabilization of eNOS, and an overall reduction in NObioavailability. Overall, a reduction in substrate (L-arginine)levels, presence of eNOS antagonists, elevatedbreakdown of NO due to OS, and decreased cofactors foreNOS, such as tetrahydrobiopterin lead to decreased NObioavailability.2 Decreased NO availability leads to excessvasomotor tone, which in turn leads to hypertension,spasm, triggers of ischemic events, and other deleterious effects on vasculature. Depletion of NO also results innuclear factor-kappa ß (NF-κB)-dependent activation ofadhesion molecules, such as selectins that promote vascularinflammation and increase the thrombotic potentialof platelets and blood coagulability, ultimately increasingthe risk of atherosclerosis and thrombosis.7 Inflammationand OS are associated with traditional and nontraditionalcardiovascular risk factors, including essential hypertension.2 Furthermore, reduced NO is associated withdecreased endothelial progenitor cell (EPC) activity andfunction, thus impairing vascular regenerative potential.8Thus, decreased NO bioavailability leads to an alterationin endothelial homeostasis, creating a vasoconstrictive,proinflammatory, proatherosclerotic, prothrombotic, andantiregenerative milieu.1

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INVASIVE EVALUATION OF ENDOTHELIAL
FUNCTION


Endothelial function can be estimated with both invasivetesting of the coronary or peripheral vasculatureand by noninvasive techniques. Assessment of coronaryendothelial function is performed by direct infusion ofendothelium-dependent vasodilators, such as acetylcholine,bradykinin, substance P, and others followedby measurement of changes in epicardial diameter andcoronary blood flow. In the setting of normal endothelialfunction, acetylcholine causes epicardial dilation andincrease in coronary blood flow. With ED, epicardialarteries constrict and flow increases to a lesser extentthan in the normal setting.1,9,10

Measurements of blood flow changes during intrabrachialarterial infusion of these endothelium-dependentvasodilators can be used to assess endothelial function inthe forearm circulation.4 During forearm plethysmography,venous drainage is briefly interrupted by inflating ablood pressure cuff, while arterial inflow is maintained.Flow measurements are recorded as endothelial vasodilatorsare infused. In the setting on normal endothelialfunction, acetylcholine, a commonly used endotheliumdependentagonist, stimulates release of NO and otherendothelium-dependent vasodilators, resulting in vasodilationof the forearm circulation.11 To study the contributionof NO to the observed vasodilation, inhibitors of NOand other endothelium-derived relaxing factors can beemployed.11-20 Finally, to study endothelium-independentfunction, NO donors, such as nitroprusside or nitroglycerineare given and blood flow responses measured.

NONINVASIVE EVALUATION OF
ENDOTHELIAL FUNCTION


Flow-mediated dilation (FMD) uses high-resolutionultrasound to assess endothelium-dependent brachial reactivity. The FMD of the brachial artery is almostentirely due to shear-mediated release of NO from theintact brachial artery endothelium and correlates withcoronary artery endothelium-dependent responses toacetylcholine, effectively serving as a surrogate markerfor coronary endothelial function.21 After transientlyinducing ischemia by cuff inflation for 5 minutes andsubsequent deflation, the resulting hyperemia increasesbrachial artery shear stress that releases NO from thehealthy endothelium and causes the brachial artery todilate. The magnitude of this FMD is proportional to theNO release from the endothelium.6
 
ENDOTHELIAL FUNCTION AND ADVERSE
CARDIOVASCULAR OUTCOMES


Endothelial dysfunction, regardless of the underlyingcause, is an independent predictor of future adversecardiovascular events.22-24 In 3,026 subjects free of cardiovasculardisease from the Multi-Ethnic Study of Atherosclerosis(MESA), followed for 5 years, each SD increasein FMD conferred a hazard ratio of 0.84 for incident cardiovascularevents. Importantly, FMD also improved netreclassification of risk when compared with the Framinghamrisk score.24 Two further studies in more selectedpopulations, including the Cardiovascular Health Studyof elderly subjects and a study by Rossi et al25 in over2,000 postmenopausal women, support these findings bydemonstrating significant association between impairedFMD and cardiovascular outcomes.24-26

ENDOTHELIAL DYSFUNCTION IN
HYPERTENSION


A traditional and widely accepted viewpoint is thathypertension is a cause rather than a consequence ofED. Acute and chronic hypertension precipitates ED.27,28The Cardiovascular Risk in Young Finns study foundthat abnormal blood pressure in youth tended to predictfuture impaired endothelial function.4 In a cross-sectionalanalysis of 3,500 middle-aged participants in MESA,hypertension was associated with a lower FMD in allethnicities.29 Finally, the degree of ED is related to themagnitude of blood pressure elevation.30,31

Multiple mechanistic studies have shown that theED observed in hypertension is associated with reducedNO bioavailability in both conductance vessels and themicrovasculature.32 Acetylcholine-mediated coronaryand forearm vasodilation is blunted in hypertension comparedwith normotensive controls.11 However, a study ina younger hypertensive population did not confirm thisfinding.33 To determine whether the reduced vasodilationwith acetylcholine is due to reduced NO bioavailability,acetylcholine infusion was repeated after administration of NG-monomethyl-L-arginine, a competitive inhibitor ofeNOS synthesis. Inhibition of acetylcholine response wasgreater in normotensive than in hypertensive subjects,indicating reduced NO bioavailability in hypertension.34Further studies demonstrated that, at least partly, thisreduction in NO activity is compensated by release ofendothelium-derived hyperpolarizing factors.34 Infusion ofvitamin C, that quenches free radicals when infused intraarterially,restored the reduced endothelium-dependentvasodilation in hypertensives, indicating the contributionof OS to the reduced NO bioavailability in hypertension.35
 
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Endothelial Dysfunction and Essential Hypertension

Endothelin-1, a powerful endogenous, endotheliumderivedvasoconstrictor peptide, is continuously releasedfrom the vascular endothelium and contributes to tonicvasomotor constrictor tone. The NO may inhibit the synthesisand hemodynamic effects of ET-1; ET-I can stimulateNO production by stimulating the endothelial ET(B)receptors.36 Blockade of ET-1 receptors, either ET(A/B) orETA, resulted in a significant increase in forearm bloodflow in hypertensive, but not in normotensive controls.Moreover, ET blockade also improved acetylcholinemediatedresponses in hypertensive patients, indicatingthat increased ET-1 activity may play a role in the pathophysiologyof hypertension.37 This increased ET-1 activitywas shown to be particularly higher in hypertensive blackparticipants compared with white subjects.38

ENDOTHELIAL DYSFUNCTION AS A
PRECURSOR TO HYPERTENSION


There is increasing evidence that ED, when presentamong normotensive subjects, may lead to future developmentof hypertension.6 For example, eNOS knockoutmice typically develop hypertension,6 infusion of NOsynthase antagonists leads to elevation of blood pressure,39 hypertensive subjects appear to have more NOS-3gene mutations,40 and normotensive offspring of hypertensivepatients demonstrate impaired endothelial function.41 In 952 postmenopausal women, free of risk factorsincluding hypertension, Rossi et al25 found that the incidenceof hypertension over a 3.6-year follow-up periodwas 5.77-fold higher in those in the lowest FMD quartilecompared with the highest, indicating a role for ED as aprecursor in the development of hypertension.42 In MESA,1869 patients without hypertension were followed overa median of 4.8 years for incident hypertension. Whilethe association between low FMD and incident hypertensionwas significant, this did not withstand multivariateadjustment for important confounders.43

BIOMARKERS OF ENDOTHELIAL DYSFUNCTION

Endothelial function can be estimated indirectly withcertain circulating biomarkers, including ADMA, oxidized low-density lipoprotein, aminothiols including glutathioneand cystine, certain adhesion molecules, such as intercellularadhesion molecule-1, endothelial microparticles(EMPs), EPCs, endothelial glycocalyx, monocyte-plateletaggregates, and others.

 
Asymmetric Dimethylarginine

Asymmetric dimethylarginine is an endogenous competitiveantagonist of NO synthase.44 Hypertensive patientshave higher ADMA levels compared with normotensive,healthy controls45 and higher ADMA levels have beenassociated with both ED and increased intima-mediathickness (IMT).46 The ADMA levels correlate withpulse wave velocity, further indicating its contributionto hypertension and increased arterial stiffness.47 TheADMA levels are also elevated in those with a high-riskfactor burden, chronic kidney disease,48 coronary heartdisease, and stroke. Importantly, higher ADMA levels areassociated with adverse long-term outcomes.49,50

Aminothiols

Oxidative stress is implicated in the pathophysiology ofED as described earlier and in multiple conditions includingCVD.50 Recent studies have shown the importanceof nonfree radical species as indicators and mediatorsof OS.51 Proteins are susceptible to oxidation throughalterations of reactive aminothiol residues and suchcovalent modifications serve to alter their cellular signalingactivity, thereby coupling redox modifications ofaminothiols to functional activity.52 Importantly, theseaminothiols can be quantified in plasma to assess theoxidant burden in vivo.53 Of these, cysteine constitutes themajor aminothiol pool extracellularly that reacts readilywith oxidants to form its oxidized disulfide cystine. Intracellularly,glutathione is a major antioxidant that helpseliminate peroxides and maintain cellular redox, and itsoxidized form is glutathione disulfide.54 We have shownthat increased OS, measured as higher levels of cystine,lower levels of glutathione, or altered ratios of oxidized toreduced aminothiols, is associated with cellular dysfunction,aging, risk factors for CVD including hypertensionand subclinical vascular disease including ED, microvasculardysfunction, arterial stiffness, increased carotidIMT, and pulmonary hypertension.52,55-62

Endothelial Progenitor Cells

Endothelial progenitor cells are bone marrow-derived stemcells with the potential to differentiate into mature vascularendothelium. Endothelial dysfunction may be consideredto be a result of a balance between the magnitude of injurydue to exposure to risk factors and the capacity for endothelialrepair.63 Although risk factor-mediated injury to the vascular endothelium is well understood, the mechanismsunderlying regeneration and the pivotal role of progenitorcells (PCs) in vascular repair and hence, to cardiovascularhealth have only recently been appreciated.63-65 TheEPCs are mononuclear cells that originate primarily (butnot exclusively) from the bone marrow and differentiateinto endothelial cells both in vitro and in vivo.66,67 The PCsreside primarily in bone marrow, circulate, and contributeto blood vessel formation during tissue repair.67-79 EndogenousPCs contribute to reendothelialization of tissuesafter endothelial injury, attenuating progression to frankatherosclerosis.80-85 Circulating PCs are multilineage, butthe most common circulating PCs are of hematopoietic andEPCs that are capable of vascular repair, largely by theirparacrine activities.86,87 Our recent studies have shownreduction in the number and migratory activity of PCs inpatients with coronary artery disease (CAD) comparedwith healthy subjects.88-93 Endothelial dysfunction correlateswith PC number and function.89,94 Importantly, alow PC count appears to be an independent predictor ofpoor outcome in patients with CAD,89,95 stroke, or acutelung injury.94-97

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Endothelial Microparticles

Endothelial microparticles are composed of endothelialcellular debris that breaks off into small membranevesicles comprised of their native cell membrane andcytoplasm. Using flow cytometry, these microparticlesare classified into EMPs, leukocyte microparticles, andplatelet microparticles (PMPs).98 The EMPs have beenused as surrogates for ED99 and been associated withdecreased NO bioavailability and with the severity ofhypertension.100-104 In 844 participants enrolled in theFramingham offspring cohort,99 circulating EMP levelswere associated with the development of traditionalcardiovascular risk factors, including hypertension.99Patients with severe hypertension, compared with thosewith mild hypertension or normal blood pressure, hadsignificantly elevated EMPs and PMPs.103

Therapeutic Targets

Both classic antihypertensive therapies, therapy targetedtoward cardiovascular risk factors and therapytargeting the NO pathway, have been studied inpatients with hypertension.105 Antihypertensive agents,including angiotensin-converting enzyme inhibitors(ACEi), angiotensin-II type I receptor blockers (ARBs),nebivolol, a third-generation beta receptor antagonist,and amlodipine, appear to improve ED in patients withhypertension.106-108 In a meta-analysis involving 1,129heterogeneous patients at increased cardiovascularrisk, ACEi and ARBs significantly improved brachial FMD compared with beta-blockers and calcium channelblockers.108 Both irbesartan and nebivolol in combinationwith hydrochlorothiazide improved vascular functionin hypertension.107 Nebivolol, in particular, has demonstratedincreased NO availability, enhanced antithromboticactivity, and improvement in markers of ED.107 Bothin patients with essential hypertension and in murinemodels, the combination of amlodipine and atorvastatinimproved vascular function.109 The BH4 acts as a cofactorof NO synthase and a scavenger for free radicals.110 Inpatients with hypertension receiving BH4 supplementation,investigators have demonstrated improvement inendothelial function.110
 
SUMMARY

Hypertension is characterized by ED, reduced NO bioavailability,and increased OS, and ED may even precedethe development of hypertension. The magnitude of EDis predictive of adverse cardiovascular outcomes, andimprovement in ED by medications and other meansmay reflect reduced risk. Markers that reflect ED arebeing studied for utility, validity, and clinical application.

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