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22 PART | I Overview
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FURTHER READING
[1] Marti CN, Gheorghiade M, Kalogeropoulos AP, Georgiopoulou VV, Quyyumi AA, Butler J. Endothelial dysfunction, arterial stiffness, and heart
failure. J Am Coll Cardiol October 16, 2012;60(16):1455–69.
Chapter 2
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Endothelial Dysfunction in Aortic
Aneurysm
Silviu I. Dumitrescu
1,2
, Mariana Jinga
Cristian Gabriel2, Ion C. Ţintoiu
1
“Titu Maiorescu” University of Bucharest, Bucharest, Romania; 2“Vasile Candea” Army's Center for Cardiovascular Diseases, Bucharest, Romania;
3
“Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania; 4“Carol Davila” Emergency Central Military Hospital, Bucharest,
Romania; 5Hospital SANADOR, Bucharest, Romania; 6“Prof. Dr. C. C. Iliescu” Emergency Institute of Cardiovascular Diseases, Bucharest, Romania;
7
“Sf. Apostol Andrei” County Clinical Emergency Hospital, Constanta, Romania
2,4,6
3,4
, Daniel Cochior
1,5
, Ecaterina Bontas6, Irinel Parepa7, Daniel Nita
2,4
,
Chapter Outline
Overview 25
Oxidative Stress 27
Graft Endothelialization 32
Conclusions 35
References 36
OVERVIEW
The aorta may be considered the biggest artery in the human body having at its origin a maximum diameter of ∼3 cm that
is the ascending aorta, the thoracic aorta (descending portion) with a diameter of ∼2.5 cm, and the abdominal aorta with
1.8–2 cm in the abdomen. Similar to the rest of arterial portions, the aortic wall is made up of three layers. First, the intima
is formed from a slight cover of endothelial cells, subendothelial connective tissue, and an internal elastic lamina. Second,
aorta has a tunica medie in large amount in comparison with the rest of peripheral arteries, being made of numerous layers
of filled with extracellular matrix (ECM) and smooth muscle cells (SMCs). Third, adventitia comprised connective tissue
surrounding vasa vasorum (small vessels) and nervi vascularis (nerves) [2]. Aortic aneurysm (AA) has a multifactorial
pathology that comprise the structural modification of arterial wall followed by its dilation and thinning with increased risk
for breaking with hemorrhagic shock. Morphologically it is described as the gradual dilation of a vessel part over 50% of
its standard diameter. Although AAs for the most part come from atherosclerotic plaques, the AA of the ascending aorta has
no correlation with lipid deposit in vessel wall. On the contrary, it has a correlation to the degeneration of the vascular wall
structures caused by any pathological hemodynamic disorder or any intrinsic lack of the cell constituents [2]. Moreover, the
dilatation of the ascending aorta mainly develops to the external arching of the vessel where there is greatest axial stress [3].
Discordantly, although the thoracic AA related with Marfan disorders mainly arise in sinuses of Valsalva secondary to physiological diastolic vortices, AA arise from the aortic root caused by distorted systolic flow connected to bicuspid valves [4].
Notable mechanisms of development, production, and breaking are still unclear. In this regard, the etiology of AA is
essentially unknown, but it is generally accepted that environmental and genetic factors contribute substantially to the risk
of AA [5]. Of these, smoking seems to be the most relevant, with a considerably higher risk for AA than for atherosclerosis
[6]. It is established that diabetes mellitus predisposes to atherosclerosis, however it provides protection for AA, especially
for aortic abdominal aneurysms (AAA) [7]. Human AA is characterized by leukocyte infiltration into adventitia and media
and depletion of vascular smooth muscle cells (VSMCs) in the media. Another relevant feature of the disorder is a decrease
in AA of wall strength caused by the breakdown of elastic fibers and the hypervascularization of aortic tissue [8].
Therefore, ECs of AA react to numerous provoking factors, together with smoking, high hypertension, angiotensin
II type 1 receptor, or receptor triggering and homogeneous spreading of the wall stress. Also, the capacity of ECs of
New Approaches to Aortic Diseases from Valve to Abdominal Bifurcation. http://dx.doi.org/10.1016/B978-0-12-809979-7.00002-X
Copyright © 2018 Elsevier Inc. All rights reserved.
25
26 PART | I Overview
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FIGURE 2.1 Multiple functions of endothelium. Green effect over arterial wall and blue effect over blood flow. From Sena CM, Pereira AM, Seiça
R. Endothelial dysfunction – a major mediator of diabetic vascular disease. Biochim Biophys Acta December 2013;1832(12):2216–31 with permission.
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generating nitric oxide (NO) is essential in the process of adjusting [9]. Also, ECs are partly responsible for AA expansion
because of “enlarged oxidative stress” that may in part settle upon by damaged “NO bioavailability” caused by endothelial
dysfunction and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase increased gene synthesis, which is caused
by raising of the frequency of transcription [9]. They also exhibit numerous molecules among “adherence molecules,
endothelin-1, selectins, regulating inflammatory infiltration and oxidative stress” [9]. Regarding inflammatory cells, these
mainly are formed of lymphocytes, polymorphonuclear neutrophils monocytes, being implicated in the aortic wall degeneration development from the starting with the releasing of proteolytic enzymes or by discharging interleukins that settle
the inflammation reaction [9]. Altogether, the arterial endothelium represents a screen between blood flow and arterial wall
with multiple functions and with bidirectional repercussions as one toward blood flow and another one over superjacent
structures. Furthermore, the aortic endothelium intervenes by blood flow, thrombotic phenomenon control, platelet activation, fibrinolysis, and VSMCs proliferation. Superjacent structures of the aortic endothelium mediate by leukocytes trafficking the vascular selective permeability, vascular tone, angiogenesis, and inflammatory process [10] (Fig. 2.1).
It is important to underline that in AA the endothelium of aortic wall undergoes the process of impairing first with
dysfunction by morphological and functional destruction of ECs through multiple mechanisms: VSMCs transformation;
median and adventitial degradation; elastin lyses; VSMCs apoptosis; modification of collagen production/collagen lyses
ratio, excessive inflammatory infiltration with involvement of matrix metalloproteinases (MMPs); collagenases activation;
and increased oxidative stress mediated by impaired NO bioavailability and NADPH oxidase overexpression [9]. Further,
endothelial dysfunction is characterized by the modification of homeostasis functions (see above) through one or more
components. Among these, increases of oxidative stress, procoagulant and proinflammatory biomarkers, molecular markers
of damage, and reduction in endothelial progenitor cells (EPCs) are established features [10]. Nonetheless, multiple studies
established the functional differences between normal endothelium function and dysfunction (see Table 2.1) [9].
Also, elevated concentrations of lactic acid, total homocysteine, and asymmetric dimethylarginine in the blood of
patients suggested a parallel development of endothelial and secondary mitochondrial dysfunction. However, concentrations of lactic and pyruvic acids exceeding reference limit were associated with the decrease in the peroxisome proliferatoractivated receptor gamma coactivator-1alpha (PGC1α) level [11]. Furthermore, Malashicheva et al. [12] showed on 30
patients with thorax AA with bicuspid aortic valve (13 patients) and with tricuspid aortic valve (17 patients) the presence of
endothelial dysfunction and the relationship with VMSCs by aneurysmal aortic wall intraoperative harvesting with cultured
ECs in a particular environment. They studied the identification markers of ECs (cluster of differentiation 31 [CD31], vWF,
and vascular endothelial cadherin) and of smooth muscle (SM actin, SM22α, calponin, and vimentin) that pointed out their
decreasing in patients with AA in comparison with normal aortic wall (Fig. 2.2). The explanation is attributable to changes
in the phenotype of ECs with repercussions on functional disturbance of ECs due to apoptosis induction and speeding up
of the reduction of cell multiplication of ECM, cellular proliferation, and migration.
Endothelial Dysfunction in Aortic Aneurysm Chapter | 2 27
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TABLE 2.1 Differences Between a Healthy and a Dysfunctional Endothelium
Healthy Endothelium Dysfunctional Endothelium
l
Vasodilatory (NO, PGI2)
l
Oxidative stress, low uric acid
l
Anticoagulant (PAI-1, vWF, P-selectin)
l
Antiinflammatory (sICAM, sVCAM, E-selectin, CRP, TNF-α,
IL-6, MCP-1)
l
Repair (EPCs), damage (CECs, MPs)
Besides impaired vasodilation (↓ nitric oxide [NO], prostaglandin I2 [PGI2]), endothelial dysfunction is characterized by increases of oxidative stress (↑nitrotyrosine and uric acid), procoagulant (↑ plasminogen activator inhibitor [PAI-1], von Willebrand factor [vWF], P-selectin), and proinflammatory biomarkers
(soluble intercellular adhesion molecule [sICAM], soluble vascular cell adhesion molecule [sVCAM], E-selectin, C-reactive protein [CRP], E-selectin, tumor
necrosis factor alpha [TNF-alpha], interleukin-6 [IL-6], monocyte chemoattractant protein-1 [MCP-1]); decrement in endothelial progenitor cells (EPCs) and
increased molecular markers of damage (circulating endothelial cells [CECs], microparticles [MPs]).
From Sena CM, Pereira AM, Seiça R. Endothelial dysfunction – a major mediator of diabetic vascular disease. Biochim Biophys Acta December
2013;1832(12):2216–31 with permission.
l
Impaired vasodilation (NO, PGI2)
l
Oxidative stress, uric acid
l
Procoagulant (PAI-1, vWF, P-selectin)
l
Antiinflammatory (sICAM, sVCAM, E-selectin, CRP, TNF-α,
IL-6, MCP-1)
l
Repair (EPCs), damage (CECs, MPs)
Another key factor in the pathophysiology of AA is prostaglandin E2 (PGE2) that induces expression of MMPs and
inhibits the production of macromolecules of the ECM [13,14]. It acts as a signaling molecule in response to proangiogenic
factors and also induces release of several angiogenic factors in a manner of positive loop [15–18]. Consequently, inhibition
or deletion of the enzymes involved in the biosynthetic pathway of PGE2 interferes in AA development in animal models
[19–23]. Initially, PGE2 biosynthesis begins with the formation of PGH2 from arachidonic acid catalyzed by cyclooxy-
genase. PGH2 is in turn isomerized by PGE-synthases (PGES) [24]. mPGES-1 is the microsomal isoform of PGES and is
brought on by proinflammatory cytokines and it appears to be an essential PGES isoenzyme engaged in PGE2 biosynthesis
in the presence of inflammatory disorders [25–27].
Endothelial telomeres—telomerases. Shortly, the telomeres of EC of aortic wall are protein structures represented
by multiplying of the sequential nucleotides TTAGGG, which are located at the distal end of the eukaryotic chromosomes preventing their degradation during mitogenesis [28]. Repetitive cell division causes the shortening of telomere
length. To prevent this shortening of telomere length in EC, an enzyme called telomerase is produced to prevent this
process after each cell division [29]. Moreover, telomere/telomerase ratio is interpreted as a cause of vascular aging and
is named the “mitotic clock” [30,31]. It should be noted that the study done by Dimitroulis et al. on 49 patients with
AAA proved a significant statistical relationship (P < .001) between the development of this pathology and decreasing
of telomerase from aortic wall (intraoperative harvesting) in comparison with the control group (sample taken from
deceased patients who had no AAA) [30]. This observation underlines the protective role of telomerase in the genesis
and development of AAA, thus constituting an explanation of the pathophysiological mechanism of initiation and progression of AAA (Fig. 2.3).
On the other hand, Cafueri et al. [32] searched in patients with AAA the telomere length from ECs of the control group
and they observed the decreasing telomere length from ECs in comparison with control group. Moreover, the telomere
length shortening is noticeable in comparison with patients with no AAA (P < .0001) [32]. Also, telomere shortening has
been seen in VSMCs from AA wall in comparison with those from normal aorta (P < .001) (Fig. 2.4).
Of note, the same study of Cafueri et al. [32] had shown that the shortening of telomere length in patients with AAA
exists in significant proportion in comparison with control group, circulating lymphocytes, and epidermal cells (see Fig.
2.5).
As well, other research studies confirm the hypothesis on telomere shortening in patients with AAA statistically significant relationship between the degree setting shortening of telomeres in circulating lymphocytes and the presence of
aneurysm [33,34].
OXIDATIVE STRESS
Oxidative stress is defined as the imbalance between the prooxidant and antioxidant status of ECs [35]. Further, this is due
to the imbalance resulted by the decreasing synthesis or by the inactivation of endothelium-derived NO conditions in which
this process favors thrombosis, activates inflammation in the aortic wall, and intimal proliferation.
28 PART | I Overview
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FIGURE 2.2 Characterization of the aortic endothelial cells (ECs) from patients with aortic aneurysm with either tricuspid aortic valve (TAV) or bicuspid aortic valve (BAV) and controls (C). Upper panel represents typical aortic EC cultures from control and aneurysmal aortas. The smooth muscle (SM
actin) staining confirms the lack of medial smooth muscle cells (SMCs) contamination in the EC culture. Vascular endothelial-cadherin (VE-cadherin),
von Willebrand factor (vWF), and platelet-EC adhesion molecule (PECAM-1, CD31) staining confirm the endothelial nature of the isolated cells. From
Malashicheva A, Kostina D, Kostina A, Irtyuga O, Voronkina I, Smagina L, Ignatieva E, Gavriliuk N, Uspensky V, Moiseeva O, Vaage J, Kostareva A.
Phenotypic and functional changes of endothelial and smooth muscle cells in thoracic aortic aneurysms. Int J Vasc Med 2016;2016:3107879. It is an
open access article.
Endothelial Dysfunction in Aortic Aneurysm Chapter | 2 29
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FIGURE 2.3 Telomerase endothelial expression in abdominal aortic aneurysms (AAAs) and control of nonaneurysmal aortic walls. Note the significantly reduced telomerase expression in AAA specimens compared to control aortas (P < .001). From Dimitroulis D, Katsargyris A, Klonaris C, Avgerinos
ED, Fragou-Plemenou M, Kouraklis G, Liapis CD. Telomerase expression on aortic wall endothelial cells is attenuated in abdominal aortic aneurysms
compared to healthy nonaneurysmal aortas. J Vasc Surg December 2011;54(6):1778–83 with permission.
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FIGURE 2.4 Telomere length of endothelial cell (EC) and vascular smooth muscle cell (VSMC) from patients with abdominal aortic aneu-
rysm measured using quantitative fluorescence in situ hydridization (Q-FISH) and immunofluorescence. (A) Aortic aneurysmatic wall derived
EC stained with anti-CD31 mAb (green). The inset shows the nuclei analyzed by Q-FISH. (B) EC interphase nuclei hybridized with Cy3-peptide nucleic
acid (PNA) telomeric probe (red signals). (C) Aortic aneurysmatic wall derived VSMC stained with anti-a-smooth muscle actin mAb (green). (D) VSMC,
nuclei hybridized with Cy3-PNA telomeric probe (red signals). 4′,6-Diamidino-2-phenylindol dichlorohydrate was used to label nuclei. From Cafueri
G, Parodi F, Pistorio A, Bertolotto M, Ventura F, Gambini C, Bianco P, Dallegri F, Pistoia V, Pezzolo A, Palombo D. Endothelial and smooth muscle
cells from abdominal aortic aneurysm have increased oxidative stress and telomere attrition. PLoS One 2012;7(4):e35312. It is an open access article.
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30 PART | I Overview
20
Percentage of 8-oxodG+ cells
Telomere length (Kb)
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16
14
12
10
8
6
4
2
0
0
FIGURE 2.5 Relationship between telomere shortening and DNA damage in blood lymphocytes from abdominal aortic aneurysm (AAA)
patients. Spearman’s correlation test. Linear regression analysis between telomere length and accumulation of reactive oxygen species induced oxida-
tive DNA damage, assessed by 8-oxo-dG staining, in blood lymphocytes from 19 AAA patients and from 23 controls. The Spearman’s rank correlation coefficient (rS) is =−0.57. From Cafueri G, Parodi F, Pistorio A, Bertolotto M, Ventura F, Gambini C, Bianco P, Dallegri F, Pistoia V, Pezzolo A,
Palombo D. Endothelial and smooth muscle cells from abdominal aortic aneurysm have increased oxidative stress and telomere attrition. PLoS One
2012;7(4):e35312. It is an open access article.
10 20 30
Spearman’s r = –0.57
40 50 60
Patients
Controls
P < 0.0001
N = 42
FIGURE 2.6 Schematic diagram showing the generation of nitric oxide (NO) and ONOO− from a coupled eNOS and an uncoupled eNOS in a normal
and a dysfunctional endothelium, respectively. eNOS, endothelial nitric oxide synthase; NAD(P)H, nicotinamide adenine dinucleotide (phosphate); TDB,
tetrahydrobiopterin. Piechota-Polanczyk A, Jozkowicz A, Nowak W, Eilenberg W, Neumayer C, Malinski T, Huk I, Brostjan C. The abdominal aortic aneu-
rysm and intraluminal thrombus: current concepts of development and treatment. Front Cardiovasc Med May 26, 2015;2:19. It is an open access article.
In AAA, the oxidative stress is partially increased and mediated by oxidative stress. On the other hand, oxidative
stress is in part increased and mediated by NO and the NADPH. The production of NO by ECs (endothelial nitric
oxide synthase [eNOS]) is made by NOS and it has a significant role in homeostasis of aorta preventing platelet aggregation and leukocyte adhesion [36]. Laminar blood flow through aorta triggers l-arginine oxygenation with increase
of eNOS. This further increases the accumulation of NO, which subsequently causes the decreasing of peroxynitrite
(ONOO−). Moreover, the turbulent blood flow debit caused by atherosclerosis produces uncoupling between arginine
and O2, resulting in endothelium dysfunction by decreasing NO [37] that may be the initial stage of aneurysm aorta
development (Fig. 2.6).
Endothelial Dysfunction in Aortic Aneurysm Chapter | 2 31
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Antiplatelet
Pulsatile bloodflow
L-arginine
L-citrulline
Guanylate
cyclase
FIGURE 2.7 Properties and production process of nitric oxide (NO) as important endothelial function nuclear factor-κB (NF-κB), vascular smooth
muscle cell (VSMC), vascular cell adhesion molecule (VCAM), and monocyte chemotactic protein-1 (MCP-1). From van den Oever IA, Raterman HG,
Nurmohamed MT, Simsek S. Endothelial dysfunction, inflammation, and apoptosis in diabetes mellitus. Mediators Inflamm 2010;2010:792393. It is an
open access article.
O
2
eNOS
NO
cGMP↑
NF-κB
VSMC
Leucocyte adhesion
VCAM-1
MCP-1
Relaxing
Antioxidant
Antiproliferative
Permeability decreasing
Antiinflammatory
Antiapoptotic
Vasodilation
It is significant to underline that NO synthesized by ECs under conditions of normal aortic wall has multiple positive effects such as antiinflammatory, prevention of platelet aggregation, as well as antioxidant properties [38]; the
permeability decreases in the arterial wall with apoptosis prevention and inhibits leukocyte adhesion by MCP-1 [39]
(see Fig. 2.7) [40].
Data studies diverge looking the role of eNOS in AA degeneration but it has been shown that inhibition of MMPs and
SMC may induce development of AA [41–43]. In summary, Piechota-Polanczyk et al. concluded that “ratio of NO concentration to ONOO− concentration” and the uniform spreading of oxidative/nitroxidative stress are involved in the essential
function in the growth of the aneurysm [1].
It should be remembered that the first results of Mai et al. [44] demonstrated that interleukin-17A (IL-17A) triggered
aortic ECs particularly via P38 mitogen-activated protein kinases (p38 MAPK) pathway. To develop this, IL-17-secreting T
helper 17 cells have been newly acknowledged as a subset of CD4(+) T helper cells that are involved in numerous inflammatory disorders and autoimmune disorders. The mechanism of how hyperlipidemic status generates IL-17A that further
triggers aortic ECs, so that monocyte attachment increases, is not known. However, the team of Mai et al. reported the
following [44]:
l Hyperlipidemia causes the oxidation of low density lipoprotein overregulated by IL-17 receptor(s) from human aortic
endothelial cells (HAECs), excluding mouse aortic endothelial cells (MAECs).
l On the other part, IL-17A triggers HAECs so that human monocyte adhesion increases in vitro. Further, the lack of
IL-17A decreases the leukocyte attachment to vascular endothelium in vivo.
l Also, IL-17A triggered HAECs and MAECs via the overregulation of proinflammatory factors such as cytokines (IL-6),
granulocyte-macrophage colony-stimulating factor, chemokine (C-X-C motif) ligand 1 (CXCL1), and CXCL2.
l Moreover, IL-17A triggers ECs specifically via the p38 MAPK pathway. The restriction of p38 MAPK in ECs reduced
IL-17A-mediated activation by promoting exhibition of the above-mentioned proinflammatory cytokines, chemokines,
and EC adhesion molecules including intercellular adhesion molecule 1.
On the other hand, CD40, chemokine (C-X3-C motif) ligand 1 (CX3CL1), and TNF-α support atheroma and neointima
development. Human vascular endothelium aortic overcontrolled CX3CL1 and TNF-α because of CD40 ligation, as well
as possible overregulated CX3CL1 in response to TNF-α [45].
On the other hand, endothelial dysfunction implicates restriction of the key ECM enzyme lysyl oxidase (LOX) and of
the vasoconstrictor protein, endothelin-1 (ET-1), whose gene expression may be accustomed by “the transcriptional activators nuclear factor kappa B (NF-κB) and activator protein-1 (AP-1)’’. Advanced glycation end products (AGEs) are a
32 PART | I Overview
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TABLE 2.2 Tissue-Engineered Vascular Grafts
Synthetic Polymers Biopolymers
Synthetic Nondegradable
Polymers
l
ePTFE (polytetrafluoroethylene),
Dacron, and polyurethanes
are currently used as synthetic
vascular grafts.
l
Dacron is most commonly used
for aortic replacement.
l
Polyurethane is better able to
match the compliance of native
vasculature, but with poor
patency.
l
Functionalization of the
polymer surfaces via chemical modification and coatings
enables improved endothelialization and thromboresistance
of the materials.
Degradable Scaffolds
l
Biodegradable polymers act as scaffolds
upon which cells and the surrounding
environment can modulate vascular
remodeling.
l
Degradable polymers, including poly-
glycolic acid, polyhydroxyalkanoates,
polycaprolactone, and polyethylene
glycol.
l
Degradable scaffold have with proteo-
lytic sites for the controlled release of
bioactive molecules from the polymer
matrix and optimized presentation of
these factors to the surrounding environment via cell-mediated degradation.
l
While degradable polymers have
enabled improved ECM production and
vascular cell infiltration into the graft
site.
l
Represent protein polymers that mimic native
characteristics of the arterial wall being a
unique method to develop a vascular graft.
l
Collagen and fibrin gels and fibers are able to
bind to critical proteins that direct cell fate,
and are therefore ideal in the formation of
artificial blood vessels.
l
Extracellular matrix (ECM) production and
mechanical integrity can be further modulated
by smooth muscle cell seeding, culture techniques, and preconditioning treatments
l
The biosynthetic machinery of microorganisms
can be exploited to produce significant quantities of recombinant protein polymers that
have been designed from primary amino acid
sequences and self-assemble into a distinct 3D
folded structure. The generation of elastinmimetic protein polymers is one such example
of a vascular tissue-engineering application.
l
Decellularized allogeneic or xenogenic tubu-
lar tissues that contain an intact and structurally organized ECM still need further advanced
studies.
Adapted from Adamopoulos C, Piperi C, Gargalionis AN, Dalagiorgou G, Spilioti E, Korkolopoulou P, Diamanti-Kandarakis E, Papavassiliou AG. Advanced
glycation end products upregulate lysyl oxidase and endothelin-1 in human aortic endothelial cells via parallel activation of ERK1/2-NF-κB and JNK-AP-1
signaling pathways. Cell Mol Life Sci April 2016;73(8):1685–98.
worsening feature of endothelial dysfunction based on the involvement of their receptor for advanced glycation (RAGE)
that triggers overregulation of MAPKs, leading to NF-κB and AP-1 amplification. Therefore, the findings of study of
Adamopoulos et al. demonstrated that AGEs activation of NF-κB- and AP-1-mediated upregulation of LOX-1 and ET-1
via the RAGE signaling cascade in human ECs provide a deformed endothelial equilibrium by damaging the endothelial
fence task, thereby changing the features of ECM ebiomechanical and cells multiplication [46].
GRAFT ENDOTHELIALIZATION
Actually, aneurysmal aortic wall replacement is done by multiple prostheses that are designed to be close to the nonaneurys-
mal vessel. Shortly, endothelialization may be made preoperatively or by cellular mechanisms generating the endothelium
of blood flow [47]. On the whole, the main arterial grafts are classified by the structure of synthetic and biological polymers
(Table 2.2).
ECs are end-differentiated cells that are not capable of cell division and expansion. Therefore, endothelial surface on
the cardiovascular implants has to mimic the natural environment for better biocompatibility [48]. With the introduction
of EPCs in 1997, rapid self-endothelialization developed extensively paving the way for various novel methods for in vivo
endothelialization on the surface of cardiovascular implants particularly “vascular grafts” and “stents” [49]. EPCs have a
relatively small population of CD circulating mononuclear cells of circulatory system available as two forms, to be precise,
early EPC and late EPC. Based on these two forms, EPCs have been exploited in two different ways: one way is to construct
and immobilize the early EPCs at the site of injury, which will secrete angiogenic cytokines that will increase the resident
ECs and the late EPCs. Another way is to construct the surface with late EPCs, which in turn promotes neoangiogenesis
and repairs the damaged site by their native ability to proliferate at high rate [50,51]. As previously stated, several active
molecules, for instance, vascular endothelial growth factor, nerve growth factor, stromal derived factor-1, and granulocytecolony stimulating factor were utilized to induce neovascularization and to repair the injury [49] (see Table 2.3 [52–61]).
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