The aortic valve was long considered a passive structure that opens and closes in response to changes in transvalvular pressure. Recent evidence suggests that the aortic valve performs highly sophisticated functions as a result of its unique microscopic structure. These functions allow it to adapt to its hemodynamic and mechanical environment. Understanding the cellular and molecular mechanisms involved in normal valve physiology is essential to elucidate the mechanisms behind valve disease. We here review the structure and developmental biology of aortic valves; we examine the role of its cellular parts in regulating its function and describe potential pathophysiological and clinical implications.
Trang 1REVIEW ARTICLE
Cellular regulation of the structure and function
of aortic valves
Ismail El-Hamamsy, Adrian H Chester, Magdi H Yacoub *
Harefield Heart Science Center, National Heart and Lung Institute, Imperial College London, United Kingdom
KEYWORDS
Aortic valve;
Endothelium;
Mechanotransduction;
Aortic valve calcification;
Interstitial cells
Abstract The aortic valve was long considered a passive structure that opens and closes in response to changes in transvalvular pressure Recent evidence suggests that the aortic valve per-forms highly sophisticated functions as a result of its unique microscopic structure These functions allow it to adapt to its hemodynamic and mechanical environment Understanding the cellular and molecular mechanisms involved in normal valve physiology is essential to elucidate the mechanisms behind valve disease We here review the structure and developmental biology of aortic valves; we examine the role of its cellular parts in regulating its function and describe potential pathophysio-logical and clinical implications
ª 2009 University of Cairo All rights reserved.
Introduction
The aortic valve lies at the junction between the left ventricle and
the aorta It opens and closes >100.000 times daily For a long
time, the aortic valve was believed to be a passive structure that
opens and closes in response to changes in transvalvular
pres-sures Although this is partly true, recent evidence clearly
dem-onstrates that the aortic valve has a tightly regulated and highly conserved architecture which allows it to perform sophisticated functions, in turn affecting systolic blood flow, ventricular workload and coronary blood flow, among other things In addition, the cellular components of the valve play an important role in maintaining normal valve architecture and composition Dysregulation in one of the elements can lead to dysfunction and dysmorphic changes of the valve In this review, we will dis-cuss the unique structure of the aortic valve We will then focus
on the role of aortic valve endothelial cells in maintaining valve structure and function and their possible role in calcified aortic valve disease, with an emphasis on clinical implications Aortic valve structure
Macroscopic structure
The aortic valve mechanism is composed of four inter-related component parts which form a functional unit: the aortic annulus, the aortic cusps, the sinuses of Valsalva and the sin-otubular junction The normal aortic valve is composed of
* Corresponding author Address: Harefield Heart Science Center,
Harefield Hospital, Hill End Road, Harefield, Middlesex, United
Kingdom Fax: +44 1895 828 900.
E-mail address: m.yacoub@imperial.ac.uk (M.H Yacoub).
2090-1232 ª 2009 University of Cairo All rights reserved Peer review
under responsibility of University of Cairo.
2090-1232 ª 2009 University of Cairo All rights reserved Peer review
under responsibility of University of Cairo.
Production and hosting by Elsevier
University of Cairo
Journal of Advanced Research
doi:10.1016/j.jare.2010.02.007
Trang 2three semi-lunar cusps that are attached to a crown-shaped
annulus at their base Adequate and coordinated opening of
the aortic valve is essential to ensure unobstructed laminar
blood flow from the left ventricle and decrease ventricular
workload in systole [1–4] Similarly, proper closure of the
cusps in diastole preserves the shape of the root and
contrib-utes to the creation of vortices in the sinuses of Valsalva, an
important determinant of adequate coronary blood flow in
diastole and in systole [5,6] The aortic valve lies in a unique
hemodynamic and mechanical environment exposing the cusps
to a wide range of stresses during the cardiac cycle, which
range from pressure, to tension and bending forces Although
aortic valve cusps are extremely thin structures, yet both sides
of the valve are exposed to different stresses, in particular
shear stress which is a major stimulus for valve endothelial
cells (VECs) The ventricular side of the cusps is exposed to
high-shear stress due to a systolic, high velocity, laminar blood
flow, whereas the aortic side of the cusps is exposed to
low-shear stress secondary to diastolic, low velocity, disturbed
blood flow VECs have the ability to sense changes in shear
stress and to translate these mechanical stimuli into biological
responses (mechanotransduction)[7] Previous studies focusing
on the vascular endothelium show that different patterns of
flow can greatly influence the response of underlying tissues
through activation of specific mechanotransduction pathways
in the endothelium, which can lead to structural changes at
the level of the vessel wall
Cellular structure
In addition to the VECs which line both sides of the cusp, the
body of the aortic valve is composed of valve interstitial cells
(VICs) lying within the extracellular matrix (ECM) (Fig 1)
VICs are composed of different cell types, namely fibroblasts,
smooth muscle cells and myofibroblasts [8] Smooth muscle
cells can exhibit both secretory and contractile properties
Along with the fibroblasts, these secretory properties are
responsible for generation, maintenance and repair of the
ECM which is mainly composed of elastin, collagen and
prote-oglycans[9] The three-dimensional microscopic architecture of
the aortic valve cusps is highly preserved between species and consists of three layers distinguishable by their chemical com-position and mechanical properties[10](Fig 1) On the aortic side lies the fibrosa, a layer rich in collagen fibers which pro-vides most of the tensile strength to the valve On the ventricu-lar side is the ventricuventricu-laris which is rich in elastin fibers, thus providing elasticity to the aortic valve Between these two layers
is the spongiosa, which represents about 60–70% of the thick-ness of the cusp and is primarily composed of proteoglycans Proteoglycans are highly hydrated, thus acting as ‘‘shock absorbers’’ during the different parts of the cardiac cycle
In addition to this basic structure of aortic valves, a popu-lation of resident stem cells lying within the cusps has recently been recognized[11] They appear to originate from the mobi-lization of hematopoietic-derived stem cells towards cardiac valves [12] Their role is not yet fully understood but they are thought to contribute to valve repair, cell regeneration,
as well as participating in valve calcification in some disease states as will be discussed later Although aortic valves are avascular structures which extract their nutrients by extraction from surrounding blood, they are richly innervated by a highly preserved network of afferent and efferent nerves which con-tribute to valve structure and function[13–15]
Cell lineage and developmental biology Aortic valve originate from endocardial cushions in the devel-oping embryo Endocardial cushions result from the migration
of endothelial cells into the cardiac jelly, followed by a process
of endothelial-to-mesenchymal transformation (EMT) which initiates what will eventually become a tri-layered aortic valve structure Migration, differentiation and delamination of these cells is a tightly controlled series of processes which depend on the activity of specific signaling molecules such as NOTCH1, transforming growth factorb (TGF-b) and the wnt/b-catenin pathway[16–19], as well hemodynamic cues[20] Importantly, the embryonic outflow tract which would ultimately yield the aortic and pulmonary valves as well as the ascending aorta and pulmonary artery are composed of cells derived from the neural crest[21] NOTCH1 is also involved in regulating the migration and differentiation of these cells in the embryo
[17] Understanding the developmental biology of the aortic valve and root has important implications for understanding normal and diseased valve physiology because most of the sig-nals that are operational during morphogenesis continue to influence growth and adaptation in postnatal life[22] For in-stance, EMT continues into adult life as demonstrated by the differentiation of mature VECs into mesenchymal cells expressing smooth musclea-actin, a process which could con-tribute to valve repair and interstitial cell regeneration[23] In addition, defining cell lineages helps explain differences in cell behaviour in response to common stimuli[24]
Aortic valves lie in a unique hemodynamic environment Blood flowing through the vasculature generates shear stress
on the luminal side of the vessel, which is entirely lined by endothelium Shear stress represents the frictional force per unit area The magnitude of shear stress can be estimated in most of the vasculature by Poiseuille’s law stating that wall shear stress is proportional to blood flow viscosity and
volu-Figure 1 Histological section showing the triple layer
architec-ture of a normal aortic valve Endothelial cells form a monolayer
on each side of the cusp Interstitial cells, a mix of fibroblasts,
smooth muscle cells (SMCs) and myofibroblasts fill the body of
the cusp They possess contractile and secretory properties and are
responsible for the synthesis and repair of the surrounding
extracellular matrix
Trang 3metric flow rate and inversely proportional to the third power
of the internal radius[25] While actual wall shear stress is very
difficult to estimate, mean shear stress along an artery is
esti-mated at 20 dynes/cm2 Unlike blood vessels, the aortic valve
is not a cylindrical structure, therefore estimation of shear
stress levels on either side of the valve requires more complex
modelling Nevertheless, the pattern of flow on the aortic and
the ventricular sides of the valve has been recognized for a long
time Leonardo da Vinci was the first to accurately describe the
laminar flow on the ventricular surface of the valve and the
dis-turbed vortex flow in the sinuses of Valsalva to which ECs on
the aortic side are exposed Estimates of actual valve shear
stresses have varied significantly in the literature[26–30] Some
have suggested that mean shear stress along the ventricular
surface of the aortic valve is around 20 dynes/cm2
[30,31], while others estimate actual peak shear stress on the
ventricu-lar surface at 80 dynes/cm2whereas it oscillates between +10
and 8 dynes/cm2on the aortic surface [32] Flow along the
ventricular surface is a high-shear laminar flow whereas it is
a low-shear disturbed flow on the aortic side
Endothelial cell heterogeneity
The endothelium is a monolayer of cells lining blood and
lym-phatic vessels which sits at the interface between all body
or-gans and blood They possess thrombogenic,
anti-adhesive, anti-proliferative and vasodilatory properties which
mainly result from the synthesis and release of nitric oxide
(NO), its major biosynthetic product and prostacyclin
(PGI2) Nevertheless, although all endothelial cells throughout
the body share the same basic properties, studies have
demon-strated a considerable amount of heterogeneity between the
endothelium from different regions of the body both at the
structural and functional levels [33] Structurally, although
most endothelial cells have a typical cobblestone appearance,
they can vary significantly in thickness, ranging from 0.1lm
in capillaries and veins to 1lm in the aorta In addition, the
number, distribution and properties of tight and adherens
junctions between them varies significantly from one vascular
bed to another reflecting endothelial adaptation to its
hemody-namic and metabolic environment Junctions are tighter in
large vessels exposed to high-shear stresses and flow rates than
small arterioles, capillaries or venules Finally, the
endothe-lium can be continuous (large arteries and veins) or
discontin-uous (liver sinusoidals), fenestrated or non-fenestrated to allow
filtration and transendothelial transport Similarly, endothelial
cells exhibit marked functional heterogeneity on several levels:
permeability, mechanotransduction pathways in response to
mechanical stimuli and angiogenesis among other functions
Aortic valve endothelial cells exhibit unique properties
Mechanotransduction and alignment
For a long time, aortic VECs were thought to play a minor
role in valve physiology because valves were considered passive
structures that opened and closed in response to changes in
transvalvular pressure More recently, several studies focusing
on the structural and functional properties of aortic VECs
sug-gest that valvular endothelium possesses unique properties
which distinguish it from other endothelial beds, particularly
the endothelium lining the aorta with which it lies in direct
continuity The most striking difference between valvular and vascular endothelial cells is cell alignment with regards
to flow orientation Whereas the vascular endothelium throughout the body aligns with the long axis of the cell par-allel to flow[34](except in areas of turbulent flow)[35], VECs are aligned perpendicular to the direction of flow [31,36]
(Fig 2) This was first described by Deck [36] by electron microscopic analysis of explanted aortic valves and further val-idated by in vitro studies[31] Cultured porcine aortic VECs were compared to aortic (vascular) endothelial cells from the same animal in response to unidirectional non-pulsatile lami-nar flow at 20 dynes/cm2 Whereas vascular cells were aligned parallel to flow after 24 h, instead, VECs aligned perpendicular
to flow even without the presence of an aligned substrate[37] These adaptations were dependent on cytoskeletal reorienta-tion, a process involving different mechanotransduction path-ways in each type of endothelium Laminar flow induced activation of Rho-kinase, phosphatidylinositol-3-kinase and
Figure 2 (a) Scanning electron microscopy of aortic valve endothelial cells forming a monolayer on the surface of the aortic cusps (1000·) The cells are tightly joined and aligned thus constituting the link between the blood milieu and the interstitial space (b) Scanning electron microscopy of aortic valve endothelial cells on the aortic side of the cusp at higher magnification (5000·) Microcilia on the surface of the cells are visible and likely act as sensors of changes in hemodynamic shear stress, in turn activating different intracellular mechanotransduction pathways
Trang 4calpain pathways in vascular endothelial cells, whereas VECs
did not require activation of the latter for cytoskeletal
reorga-nization[31]
Gene expression profile
VECs also appear to have a higher proliferation rate than
vas-cular endothelial cells[38] Furthermore, both sets of cells
pos-sess different transcription profiles In a study examining the
transcription profiles of 847 genes, there was common
expres-sion of 55 activated genes whereas a further 48 genes were
dif-ferentially activated Among those genes with a higher
activation in the valvular ECs were transcription factors
associated with higher proliferation rate such as jun D and
protein kinase C [38] Notably, both vascular endothelium
and VECs expressed markers linked with calcification such
as osteonectin, bone morphogenic protein-7 and -9 (BMP-7
and BMP-9) Differences in gene expression profile between
vascular and valvular endothelium were further validated by
another study showing different gene expression profiles in
re-sponse to shear stress stimulation of cultured porcine aortic
endothelial cells or VECs [37] In that study, Butcher et al
showed preferential expression of genes associated with
chon-drogenesis by VECs whereas vascular endothelial cells
ex-pressed more genes associated with osteogenesis Shear stress
reduced the expression of osteogenic genes[37]
Aortic valve endothelial cells are different on both sides of the
valve
Aortic valve calcification is a major clinical problem in elderly
patients and those with bicuspid aortic valve disease With
in-creased life expectancy, improved diagnostic techniques and
better global access to health care, the incidence of aortic valve
calcification is expected to triple within the next 40 years[39],
making it one of the major sources of cardiovascular disease
In recent years, it has become increasingly clear that aortic
valve calcification is an active cell-driven process that shares
many similarities with atherosclerosis Among those, early
endothelial dysfunction has been shown to act as an initial
occurrence in the cascade of events leading to valve
calcifica-tion[40] Histologically, aortic valve calcification occurs
exclu-sively on the aortic side of the valve suggesting that perhaps
VECs on the aortic side are less resistant to calcification than
those on the ventricular side (Fig 3) Simmons et al developed
an innovative technique to separately analyze gene expression
of VECs from either side of the valve[41] This modified
Haut-chen technique for en face isolation of VECs allowed reliable
extraction of high quality mRNA for analysis of gene
expres-sion profiles between both aortic and ventricular VECs The
authors reported the differential expression of 584 genes
in situ between both sides of the valve[42] VECs derived from
the aortic side expressed fewer genes associated with inhibition
of calcification such as oteoprotegerin, parathyroid hormone
and chordin, a protein that inhibits the osteoinductive effects
of BMPs[42] In addition, aortic-sided VECs showed increased
expression of transcripts linked with bone formation including
BMP4 However, this was balanced by a higher expression of
antioxidative and anti-inflammatory genes on the aortic side
Notably, there were higher levels of endothelial nitric oxide
synthase (eNOS) on the aortic side of the valve Because the
mRNA obtained in this study originated directly from freshly
explanted aortic valves, it represented a good picture of in situ gene expression in normal valves However, the gene array used was a human array and only covered 12,000 genes Cur-rently, porcine gene arrays that cover >24,000 genes are com-mercially available and could provide additional clues into the functional side-specificity of aortic VECs This will be greatly enhanced following the full sequencing of the pig genome which is expected towards the end of 2009 We have recently succeeded in separately isolating aortic VECs from either side
of the valve and culturing them in vitro We are currently studying their intrinsic properties in vitro in an effort to deter-mine their responses to various mechanical and pharmacolog-ical stimuli as well as modifications in gene expression profiles Differences in flow patterns between both sides of the valve
as described earlier are sensed by a thin layer of glycoproteins
on the luminal surface of endothelial cells called the glycoca-lyx, which communicates with the cytoskeleton and can activate several signaling pathways in response to flow
[25,43–45] This process of translating mechanical stimuli into biological signals is commonly termed mechanotransduction Studies on vascular endothelial cells have demonstrated that differences in shear stress translate into activation of different signaling pathways, illustrated by the presence of atheroscle-rotic plaques in areas of low wall shear stress in the vasculature such as the carotid artery bifurcation One of the major acti-vated signaling pathways is the nuclear factor-kB (NFkB), a highly conserved transcription factor which translocates to the nucleus when activated, triggering the production of pro-inflammatory molecules[46,47] To date, the glycocalyx has not been identified or characterized on the surface of aortic valves Identification of the specific cell-surface molecules which contribute to mechanotransduction in VECs could open new avenues into understanding disease processes in condi-tions of abnormal shear stresses on the valves
The different mechanotransduction pathways involved on either side of the valve in response to different patterns of flow have yet to be described (Fig 4) Recently, a flow apparatus consisting of a cone and plate was developed to allow
in vitro reproduction of aortic and ventricular flow patterns
Figure 3 Histological section of a calcified human aortic valve from a patient with calcified aortic valve stenosis Tripp–McKay silver impregnation staining shows the calcium nodule on the aortic side of the cusp, below the endothelial layer
Trang 5on aortic valves [32] Preliminary studies using that system
show that unlike vascular endothelium, VECs on both the
aor-tic and ventricular side were not activated by exposure to
bidi-rectional oscillatory flow (reproducing flow on the aortic side),
as illustrated by an absence of vascular adhesion molecule-1
(VCAM-1), intercellular adhesion molecule-1 (ICAM-1),
E-selectin and BMP4[48] However, exposure of aortic-sided
endothelium to high-shear laminar flow (ventricular flow)
resulted in endothelial activation characterized by expression
of these inflammatory markers[48] This underscores the
no-tion that both sets of VECs activate different
mechanotrans-duction pathways in response to similar mechanical stimuli
Endothelial cells play an important role in normal aortic valve
function
In addition to their traditional role in preserving an
anti-adhe-sive and anti-proliferative surface, VECs are actively involved
in the regulation of aortic valve function As discussed
previ-ously, mechanical strain on the surface of the cusps as well
as coronary blood flow are both affected by the shape and
stiffness of the aortic valve cusps[5,6,49,50] Aortic valve
cal-cification has been shown to occur in areas of high mechanical
strains on the valve, namely the commissures, the base of the
cusps and the free edges[51] Changes in the stiffness of the
aortic valve cusps could significantly impact stress magnitude
and distribution along the surface of the cusps We have
recently demonstrated the role of the endothelium in
regulat-ing the mechanical properties of the aortic valve in vitro usregulat-ing
a biaxial micromechanical testing system [52] In that study,
aortic valve cusps were stimulated with endothelin-1 (ET-1),
a potent vasoconstrictor peptide which is released by
endothe-lial cell or serotonin (5-HT), an agent which mediates the re-lease of nitric oxide by the endothelium Addition of ET-1 resulted in a 25% increase in the elastic modulus (stiffness)
of aortic valve cusps, whereas addition of 5-HT induced a 30% decrease in valve stiffness Interestingly, addition of cyto-chalasin D, an inhibitor of actin polymerization reversed the increase in valve stiffness in response to ET-1, highlighting the role of the contractile elements in the VIC population and the communication between VECs and VICs in the valve These findings suggest that the aortic valve is capable of auto-regulation, but that it is also subject to overall systemic conditions such as hypertension or diabetes which are often accompanied by dysregulated concentrations of circulating vasoactive agents As previously stated, hypertension, smoking and diabetes are among the risk factors associated with aortic valve calcification In addition to their direct metabolic effects, this could be secondary to their effect in modulating valve stiff-ness which could lead to abnormal stress distribution along the cusps[53]
Is the aortic valve endothelium involved in valve calcification?
To date, no definitive link between VECs and valve calcifica-tion has been directly established Nevertheless, a number of studies have recently demonstrated a potential causal relation-ship Taken together, this cumulative weight of evidence strongly suggests that the endothelium plays an active role in the cellular and molecular events involved in aortic valve cal-cification As mentioned earlier, Simmons et al showed a dif-ferent pattern of gene expression between VECs on either side
of the valve characterized by a higher expression of pro-calcific genes and on the aortic side of the valve[42] In addition, an
Figure 4 Illustration of some of the mechanostransduction pathways activated inside VECs in response to shear stress Cells sense shear stress through mechanosensors on their surface which trigger activation of intracellular mediators such as nuclear factor-kB (NFkB) or Rho, which lead to synthesis of various signaling molecules which are either directly released by the cells or translocate to the nucleus and induce modifications in gene expression The pathways activated result in different effects including modified chemotaxis, cell adhesion and expression of inflammatory markers (adapted from[46,62])
Trang 6in vitro study examining the role of strain on VEC activation
in vitro showed that overstretching of the cells induces the
expression of adhesion molecules, an important initial event
leading to local inflammation which is characterized by
mono-cyte chemotaxis and infiltration [54] Physiological strain
which was evaluated as a cyclical stretch of 10% did not affect
VECs, whereas 20% cyclical strain on resulted in expression of
VCAM-1, ICAM-1 and E-selectin[54], similar to what is
com-monly observed in calcified human valves In addition, a recent
study by Kennedy et al using an in vitro model of VIC
calci-fication such as described by us and others [55,56],
demon-strated that addition of nitric oxide donors or agents raising
intracellular cyclic guanosine monophosphate (cGMP) levels
led to a decrease in the formation of calcified nodules in
re-sponse to stimulation with osteogenic medium and
transform-ing growth factorb (TGFb), an important pathogenic element
in vascular and valvular calcification[57] Furthermore, in our
laboratory, we developed an in vitro model of aortic valve
cal-cification by exposing whole cusp tissue to osteogenic medium
for a period of 10–14 days Preliminary data show that similar
to what is observed in vivo, calcium nodules (characterized by
positive Alizarin-red staining) were present on the aortic side
of the valve More importantly, endothelial denudation of
the cusp surface using a cell scraper or addition of L-NAME
(an inhibitor of nitric oxide synthase) led to a significant
in-crease in the number of Alizarin-red positive nodules (data
not published)
Taken together, these results strongly suggest that a healthy
and functional valve endothelium acts an important first-line
barrier against valve calcification The endothelium appears
to exert its effect by a combination of effects on overall valve
structure and function It can modify the mechanical
proper-ties of the cusps which might have an important effect in
pro-tecting the leaflets from high mechanical stresses These
elevated stresses on the cusps can eventually lead to areas of
‘‘micro-tears’’ or interruption of the endothelial barrier As a
consequence, the endothelium which appears to protect
against calcification by communicating with the VICs in a
par-acrine way loses this capacity and exposes the VICs to
osteo-genic stimuli VICs have been shown to respond to direct
osteogenic stimuli by expressing a high number of activated
fibroblasts, the myofibroblasts These cells have the capacity
to transdifferentiate into osteogenic-like cells and produce
hydroxyapatite
Clinical implications
The importance of the living cellular environment in the valve
is aptly illustrated in patients requiring aortic valve
replace-ment surgery[58] Most aortic valve prostheses are acellular,
including tissue valve prostheses and even aortic homografts
which become rapidly decellularized These different valve
sub-stitutes are hampered by their limited durability due to
struc-tural valve deterioration [59] However, one operation
consists of replacing the diseased aortic root with the patient’s
pulmonary root: the Ross procedure It is the only operation
which guarantees long-term viability of the neo-aortic valve
This in turn directly translates into a significant benefit to
the patients in terms of survival, freedom from reoperation,
freedom from valve-related complications and quality of life
[60] We believe that this observed benefit is in large part due
to the ability of the neo-aortic root to adapt to its hemody-namic environment, to respond to various stimuli and to con-tinuously repair in a similar fashion to normal valves[61] Nevertheless, the Ross procedure is a technically complex operation which results in uneven results among different centers around the world Therefore, a more reproducible approach is necessary This will be best addressed by progresses
in heart valve tissue engineering Although some promising first steps were made, more is required both in understanding normal valve physiology and combining biological, biochemi-cal, engineering, physics and nanotechnology expertise to develop a biocompatible tri-layered aortic valve substitute that can reproduce the sophisticated functions of the normal aortic valve We and others are making big strides towards reaching that goal and are optimistic that a fully tissue-engineered heart valve will eventually become a viable option for patients undergoing valve replacement surgery
Finally, therapeutic strategies targeting the endothelium could have a major impact on the treatment of aortic valve dis-ease Various agents have shown promise in reducing, revers-ing or slowrevers-ing the progression of vascular atherosclerotic disease, including statins[55] In addition to their lipid-lower-ing effect, statins exhibit a range of pleiotropic effects which can have a direct impact on endothelial function and address the different pathological mechanisms associated with hyper-cholesterolemia which lead to valve calcification, such as apop-tosis [62] Thus far, most clinical trials have shown mixed results for the use of statins in patients with aortic valve dis-ease However, it is possible that statin administration needs
to be initiated as primary prevention in order to show a reduc-tion in the incidence of aortic valve disease In the mean time, search for other more endothelial-specific compounds should
be undertaken and will only be possible following a thorough understanding of the specific biology of VECs
Conclusion The aortic valve lies at a critical junction in the circulatory sys-tem and is subjected to extremes of mechanical and hemody-namic forces with every cardiac cycle Yet, in the majority of people, these thin structures never fail This is a result of the highly sophisticated cellular and molecular functions of aortic valves We have overviewed the contribution of the endothe-lium to the structure and function of aortic valves in health and disease As our knowledge of these cells both in vitro and in vivo increases, understanding of the pathophysiological mechanisms of aortic valve disease will become clearer It is hoped that this will open opportunities towards targeted ther-apeutic approaches to aortic valve disease, starting with tissue engineering of heart valves
References
[1] Higashidate M, Tamiya K, Beppu T, Imai Y Regulation of the aortic valve opening In vivo dynamic measurement of aortic valve orifice area J Thorac Cardiovasc Surg 1995;110(2): 496–503.
[2] Dagum P, Green GR, Nistal FJ, Daughters GT, Timek TA, Foppiano LE, et al Deformational dynamics of the aortic root: modes and physiologic determinants Circulation 1999;100(19 Suppl.):II54–62.
Trang 7[3] Lansac E, Lim HS, Shomura Y, Lim KH, Rice NT, Goetz W,
et al A four-dimensional study of the aortic root dynamics Eur
J Cardiothorac Surg 2002;22(4):497–503.
[4] Yacoub MH, Kilner PJ, Birks EJ, Misfeld M The aortic outflow
and root: a tale of dynamism and crosstalk Ann Thorac Surg
1999;68(3 Suppl.):S37–43.
[5] Davies JE, Parker KH, Francis DP, Hughes AD, Mayet J What
is the role of the aorta in directing coronary blood flow? Heart
2008;94(12):1545–7.
[6] Bellhouse BJ, Bellhouse FH Mechanism of closure of the aortic
valve Nature 1968;217(5123):86–7.
[7] White CR, Frangos JA The shear stress of it all: the cell
membrane and mechanochemical transduction Philos Trans R
Soc London B Biol Sci 2007;362(1484):1459–67.
[8] Taylor PM, Batten P, Brand NJ, Thomas PS, Yacoub MH The
cardiac valve interstitial cell Int J Biochem Cell Biol
2003;35(2):113–8.
[9] Yacoub MH, Cohn LH Novel approaches to cardiac valve
repair: from structure to function: part I Circulation 2004;109(8):
942–50.
[10] Stella JA, Sacks MS On the biaxial mechanical properties of the
layers of the aortic valve leaflet J Biomech Eng 2007;129(5):
757–66.
[11] Chen JH, Yip CYY, Sone ED, Simmons CA Identification and
characterization of aortic valve mesenchymal progenitor cells
with robust osteogenic calcification potential Am J Pathol
2009;174:1109–19.
[12] Visconti RP, Ebihara Y, LaRue AC, Fleming PA, McQuinn TC,
Masuya M, et al An in vivo analysis of hematopoietic stem cell
potential: hematopoietic origin of cardiac valve interstitial cells.
Circ Res 2006;98(5):690–6.
[13] Chester AH, Kershaw JDB, Sarathchandra P, Yacoub MH.
Localisation and function of nerves in the aortic root J Mol Cell
Cardiol 2008;44(6):1045–52.
[14] El-Hamamsy I, Yacoub MH, Chester AH Neuronal regulation
of aortic valve cusps Curr Vasc Pharmacol 2009;7(1):40–6.
[15] Marron K, Yacoub MH, Polak JM, Sheppard MN, Fagan D,
Whitehead BF, et al Innervation of human atrioventricular and
arterial valves Circulation 1996;94(3):368–75.
[16] High FA, Epstein JA The multifaceted role of Notch in cardiac
development and disease Nat Rev Genet 2008;9(1):49–61.
[17] Niessen K, Karsan A Notch signaling in cardiac development.
Circ Res 2008;102(10):1169–81.
[18] Lee YM, Cope JJ, Ackermann GE, Goishi K, Armstrong EJ,
Paw BH, et al Vascular endothelial growth factor receptor
signaling is required for cardiac valve formation in zebrafish.
Dev Dynam 2006;235(1):29–37.
[19] Armstrong EJ, Bischoff J Heart valve development: endothelial
cell signaling and differentiation Circ Res 2004;95:459–70.
[20] Butcher JT, McQuinn TC, Sedmera D, Turner D, Markwald
RR Transitions in early embryonic atrioventricular valvular
function correspond with changes in cushion biomechanics that
2007;100(10):1503–11.
[21] Jiang X, Rowitch DH, Soriano P, McMahon AP, Sucov HM.
Fate of the mammalian cardiac neural crest Development
2000;127(8):1607–16.
[22] Garg V, Muth AN, Ransom JF, Schluterman MK, Barnes R,
King IN, et al Mutations in NOTCH1 cause aortic valve
disease Nature 2005;437(7056):270–4.
[23] Paranya G, Vineberg S, Dvorin E, Kaushal S, Roth SJ, Rabkin
E, et al Aortic valve endothelial cells undergo transforming
growth factor-beta-mediated and non-transforming growth
factor-beta-mediated transdifferentiation in vitro Am J Pathol
2001;159(4):1335–43.
[24] Topouzis S, Majesky MW Smooth muscle lineage diversity in
the chick embryo Two types of aortic smooth muscle cell differ
in growth and receptor-mediated transcriptional responses
to transforming growth factor-beta Dev Biol 1996;178(2): 430–45.
[25] Davies PF Flow-mediated endothelial mechanotransduction Physiol Rev 1995;75(3):519–60.
[26] Stevenson DM, Yoganathan AP, Williams FP Numerical simulation of steady turbulent flow through trileaflet aortic heart valves – II Results on five models J Biomech 1985;18(12):909–26.
[27] Stevenson DM, Yoganathan AP Numerical simulation of steady turbulent flow through trileaflet aortic heart valves – I.
1985;18(12):899–907.
[28] Walburn FJ, Stein PD Wall shear stress during pulsatile flow distal to a normal porcine aortic valve J Biomech 1984;17(2):97–102.
[29] Nandy S, Tarbell JM Measurement of wall shear stress distal to
a tri-leaflet valve in a rigid model of the aortic arch with branch flows J Biomech Eng 1988;110(3):172–9.
[30] Weston MW, LaBorde DV, Yoganathan AP Estimation of the shear stress on the surface of an aortic valve leaflet Ann Biomed Eng 1999;27(4):572–9.
[31] Butcher JT, Penrod AM, Garcı´a AJ, Nerem RM Unique morphology and focal adhesion development of valvular endothelial cells in static and fluid flow environments Arterioscler Thromb Vasc Biol 2004;24(8):1429–34.
[32] Sucosky P, Padala M, El Hammali A, Balachandran K, Hanjoong JO, Yoganathan AP Design of an ex vivo culture system to investigate the effects of shear stress on cardiovascular tissue J Biomech Eng 2008;130(3):035001.1.
[33] Aird WC Mechanisms of endothelial cell heterogeneity in health and disease Circ Res 2006;98(2):159–62.
[34] Imberti B, Seliktar D, Nerem RM, Remuzzi A The response of endothelial cells to fluid shear stress using a co-culture model of the arterial wall Endothelium 2002;9(1):11–23.
[35] Passerini AG, Polacek DC, Shi C, Francesco NM, Manduchi E, Grant GR, et al Coexisting proinflammatory and antioxidative endothelial transcription profiles in a disturbed flow region of the adult porcine aorta Proc Natl Acad Sci USA 2004;101(8): 2482–7.
[36] Deck JD Endothelial cell orientation on aortic valve leaflets Cardiovasc Res 1986;20(10):760–7.
[37] Butcher JT, Tressel S, Johnson T, Turner D, Sorescu G, Jo H,
et al Transcriptional profiles of valvular and vascular endothelial cells reveal phenotypic differences: influence of shear stress Arterioscler Thromb Vasc Biol 2006;26(1):69–77 [38] Farivar RS, Cohn LH, Soltesz EG, Mihaljevic T, Rawn JD, Byrne JG Transcriptional profiling and growth kinetics of endothelium reveals differences between cells derived from porcine aorta versus aortic valve Eur J Cardiothorac Surg 2003;24(4):527–34.
[39] Yacoub MH, Takkenberg JJ Will heart valve tissue engineering change the world? Nat Clin Pract Cardiovasc Med 2005;2(2): 60–1.
[40] Otto CM, Kuusisto J, Reichenbach DD, Gown AM, O’Brien
KD Characterization of the early lesion of ‘degenerative’ valvular aortic stenosis Histological and immunohistochemical studies Circulation 1994;90(2):844–53.
[41] Simmons CA, Zilberberg J, Davies PF A rapid, reliable method
to isolate high quality endothelial RNA from small spatially-defined locations Ann Biomed Eng 2004;32(10):1453–9 [42] Simmons CA, Grant GR, Manduchi E, Davies PF Spatial heterogeneity of endothelial phenotypes correlates with side-specific vulnerability to calcification in normal porcine aortic valves Circ Res 2005;96(7):792–9.
[43] Lopez-Quintero SV, Amaya R, Pahakis M, Tarbell JM The endothelial glycocalyx mediates shear-induced changes in hydraulic conductivity Am J Physiol Heart Circ Physiol 2009;296(5):H1451–6.
Trang 8[44] Pahakis MY, Kosky JR, Dull RO, Tarbell JM The role of
endothelial glycocalyx components in mechanotransduction of
fluid shear stress Biochem Biophys Res Commun 2007;355(1):
228–33.
[45] Wang N, Butler JP, Ingber DE Mechanotransduction across
the cell surface and through the cytoskeleton Science
1993;260(5111):1124–7.
[46] Helderman F, Segers D, de Crom R, Hierck BP, Poelmann RE,
Evans PC, et al Effect of shear stress on vascular inflammation
and plaque development Curr Opin Lipidol 2007;18(5):527–33.
[47] Partridge J, Carlsen H, Enesa K, Chaudhury H, Zakkar M,
Luong L, et al Laminar shear stress acts as a switch to regulate
divergent functions of NF-kappa B in endothelial cells FASEB
J 2007;21:3553–61.
[48] Sucosky P, Balachandran K, Elhammali A, Jo H, Yoganathan
AP Altered shear stress stimulates upregulation of endothelial
VCAM-1 and ICAM-1 in a BMP-4 and TGF-beta1-dependent
pathway Arterioscler Thromb Vasc Biol 2009;29(2):254–60.
[49] Robicsek F, Thubrikar MJ Role of sinus wall compliance in
aortic leaflet function Am J Cardiol 1999;84(8):944, 6, A7.
[50] Thubrikar MJ, Nolan SP, Aouad J, Deck JD Stress sharing
between the sinus and leaflets of canine aortic valve Ann Thorac
Surg 1986;42(4):434–40.
[51] Grande KJ, Cochran RP, Reinhall PG, Kunzelman KS Stress
variations in the human aortic root and valve: the role of
anatomic asymmetry Ann Biomed Eng 1998;26(4):534–45.
[52] El-Hamamsy I, Balachandran K, Yacoub MH, Stevens LM,
Sarathchandra P, Taylor PM, et al Endothelium-dependent
regulation of the mechanical properties of aortic valve cusps J
Am Coll Cardiol 2009;53:1448–55.
[53] Melina G, Horkaew P, Amrani M, Rubens MB, Yacoub MH,
Yang GZ Three-dimensional in vivo characterization of
calcification in native valves and in freestyle versus homograft
aortic valves J Thorac Cardiovasc Surg 2005;130(1):41–7.
[54] Metzler SA, Pregonero CA, Butcher JT, Burgess SC, Warnock
JN Cyclic strain regulates pro-inflammatory protein expression
in porcine aortic valve endothelial cells J Heart Valve Dis 2008;17(5):571, 577 [discussion 578].
[55] Osman L, Yacoub MH, Latif N, Amrani M, Chester AH Role of human valve interstitial cells in valve calcification and their response to atorvastatin Circulation 2006;114(1 Suppl.):I547–52.
[56] Mathieu P, Voisine P, Pepin A, Shetty R, Savard N, Dagenais F Calcification of human valve interstitial cells is dependent on alkaline phosphatase activity J Heart Valve Dis 2005;14(3): 353–7.
[57] Kennedy JA, Hua X, Mishra K, Murphy GA, Rosenkranz AC, Horowitz JD Inhibition of calcifying nodule formation in cultured porcine aortic valve cells by nitric oxide donors Eur J Pharmacol 2009;602(1):28–35.
[58] Yacoub MH, Cohn LH Novel approaches to cardiac valve repair: from structure to function: part II Circulation 2004;109(9):1064–72.
[59] El-Hamamsy I, Zaki M, Stevens LM, Clark L, Rubens M, Yacoub MH Rate of progression and functional significance of aortic valve and root calcification following freestyle versus homograft aortic root replacement: results from a prospective randomized trial Circulation 2008;118:S942.
Sarathchandra P, Bogers AJ, et al An evaluation of the Ross operation in adults J Heart Valve Dis 2006;15(4):531–9 [61] Yacoub MH The loss operation– an evolutionary tale Asian Cardiovasc Thorac Amm 2006;14(1):1–2.
[62] Rajamannan NM, Sangiorgi G, Springett M, Arnold K, Mohacsi T, Spagnoli LG, et al Experimental hypercholes-terolemia induces apoptosis in the aortic valve J Heart Valve Dis 2001;10(3):371–4.