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TABLE 2.3 Tissue Engineering of Endothelialization
https://t.me/med1917
In vitro endothelialization
In situ endothelialization
With autologous vascular cells [53–55]
l
Coculture with fibroblasts and smooth muscle cells (produce extracellular matrix [ECM])
l
Mature endothelial cells [56]
l
Endothelial progenitor cells (EPCs) [56]
l
Pluripotent stem cells [56]
Chemical coatings [57]
l
Collagen
l
Fibronectin
l
Laminin
l
Poly-l-lysine
l
Gelatin and ECM
Chemical bonding [57]
l
Heparin
l
Arginine–glycine–aspartate (RGD) and lectins
l
RGD
l
Mussel adhesive protein (MAP)
Circulating endothelial cells [58]
l
EPCs [59–61]
l
Surface modification (shear stress preconditioning and electrostatic charging)
l
Self-endothelialisation of biomaterials [51]
Endothelial Dysfunction in Aortic Aneurysm Chapter | 2 33
Adapted from Schopka S, Schmid T, Schmid C, Lehle K. Current strategies in cardiovascular biomaterial functionalization. Materials 2010;3(1):638–55. It is
an Open access Article.
The arterial endothelialization of arterial grafts by tissue engineering techniques represents a significant goal in the
prosthetics engineering procedures because of its multiple protective properties of ECs in the particular prevention of
thrombosis, reducing neointimal hyperplasia and the controlling the inflammatory phenomenon of neovascularization, etc.
[62]. Importantly, this endothelialization is based on the activity of EPCs [63] by their content in bioactive peptides that
participate in the formation of the endothelium bioactive peptides by their linear adherence [64].
Cellular endothelialization treatment of biologic or synthetic sides represents an important approach to increase “biocompatibility of implantable biomaterials” [65]. Specifically, cellular endothelialization could use various cellular types
like “endothelial cells, SMCs, fibroblastic cells, or macrophages.” EC resources for tissue engineering are mature ECs,
EPCs, or pluripotent stem cells [56]. Sources for autologous vascular cells are superficial veins, bone marrow punctuation, peripheral blood and adipose tissue that may be harvested from patients. Separation of autologous vascular cells is
restricted as a consequence of a number of causes, which comprise inadequate vessel condition and limited multiplying
ability of harvested primary cells and technical hazards to obtain “pure populations of vascular cells.” It is important to
note that a precondition for total coating of the total surface of artificial grafts with vascular cells is the development of
“the cells using bioreactors” [66,67] or “magnetic seeding” [68]. Fibronectin coating is significant for the attachment
of ECs, although fibroblasts have the capacity to manufacture their individual ECM proteins to permit enhanced cell
attachment [69]. Coculture of fibroblasts and SMCs is an alternative to the manufacture of ECM for stable “EC seeding”
[70]. Consequently, in cardiovascular surgery, in vitro endothelialization is just realistic previous to particular surgical
techniques. In vitro endothelialization appears as an applicable clinical technique for heart valve surgery but also for
vascular graft replacement surgery.
It is well known that for over 40 years in humans, “transanastomotic endothelial ingrowth” does not go beyond the
bounds of over 1–2 cm after years of implantation [71]. As a result, approaches are compulsory to ensure fast in vivo
34 PART | I Overview
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FIGURE 2.8 Schematic representation of the proposed mechanism by which graft biomaterials contribute to the modulation of vascular tissue remodeling. The interaction of stem cells with injure tissue may lead to activation of signal molecules that improve vascular tissue repairing injury (e.g.,
by increasing the adhesion, migration, proliferation, differentiation, and endothelialization). ADSCs, adipose-derived stem cells; BDNF, brain-derived
neurotrophy factor; bFGF, basic fibroblast growth factor; CSTSs, cardiac mesenchymal stem cells; eNOS, endothelial nitric oxide; EPCs, endothelial
progenitor cells; FAK , focal adhesion kinase; iPSs, pluripotent stem cells; MDSCs, muscle-derived stem cells; MMP-2, matrix metalloproteinase-2; MSCs,
mesenchymal stem cells; PDECs, progenitor-derived endothelial cells; PI3K, phosphoinositide 3-kinases; SDF-1α, stromal-derived factor-1α; α-SMA,
α-smooth muscle actin; vWF, von Willebrand factor. From Huang HS, Hsu SH. Current advances of stem cell-based approaches to tissue-engineered
vascular grafts. OA Tissue Eng March 01, 2013;1(1):2. It is an open access article.
endothelialization after implantation of the prosthetic grafts. As mentioned earlier, appropriate ECs are CECs, EPCs [58],
and EPCs characterized by their cluster of differentiation as mesenchymal stem cells [59–61]. The mechanism is based
on the acquiring of cells from the blood and to seed cells without delay on the graft surfaces. Further, the seeded cells are
supposed to increase and expand and make a distinction to assemble antithrombotic sides and viable tissues. Among them,
particularly EPCs and the bone marrow–derived monocyte lineage cells have become known as the potential resources for
prosthetic graft seeding [72].
Potential mechanisms of protective effects of seeded ECs on intimal hyperplasia in vascular prosthesis have been studied. First, the production of NO, C-type natriuretic peptide, and heparan sulfate by ECs leads to inhibition of proliferation
and migration of VSMCs. Second, the production of NO and prostacyclin (PGI2) by ECs inhibits platelet aggregation, with
subsequent reduction in release of platelet-derived growth factor and thromboxane A2 by platelets. Third, the mechanical
barrier formed by ECs prevents infiltration of leukocytes, thereby reducing the production of growth-stimulation cytokines
including TNF-α and transforming growth factor-beta [72].
Nevertheless, further studies are needed due to inconsistent data results from animal studies and clinical trials on
“tissue-engineered biomaterials” [73].
A variety of approaches as well as in vitro endothelialization of the graft have been employed to surmount these problems but it has been underlined that a small number of in vivo results have been acquired even if different in vitro models
were not able to prove that the EC functions are preserved similarly to the normal endothelium [74,75] and to prevent
thrombosis and hyperplasia [62]. This states that the engineered neoendothelium is not able to control this processes when
it comes, and this is why current studies aim to prove that the EC adhesion optimization would prevent the intragraft
thrombosis. Further, Huang et al. propose a sequential mechanism of muscle tissue remodeling and vascular grafts from
endothelialization of vascular grafts starting with the initial stage of EPC [76] (see Fig. 2.8).
Endothelial Dysfunction in Aortic Aneurysm Chapter | 2 35
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Moreover, several studies revealed that when blood gets in contact with a different covering surface other than
the endothelium, there is an elevated thrombosis risk. These conditions can be related also with releasing of the
connected ECs that can separate immediately after implantation because of the shear stress correlated with blood
flow [77]. The EC layer inhibit intensely thrombosis by thrombomodulin receptors, heparin sulfate, proteoglycans,
secretion of NO, prostacyclin, protein S, and tissue plasminogen activator (t-PA). Aside from these findings, the
endothelium has the primary role in blood pressure regulation, angiogenesis, and adhesion and transmigration of
inflammatory cells. Therefore, it is regarded as an essential factor for sustaining good “the long-term patency.”
Despite the fact that ECs have restricted ability for regeneration and used up their regeneration after more or less 70
cell cycles, this has been incriminated to the hypothesis that endothelialization of vascular grafts takes place via one
of four mechanisms:
l Seeding ECs onto graft [78–84],
l EC migration from adjacent artery [78,85–91],
l Through deposition of circulating detached ECs or capillaries [79,91–93],
l Via ingrowth of capillaries through porous grafts [94].
In view of the fact that Herring anticipated from 1978 “the method of seeding ECs” on the luminal side of synthetic
conduits [95,96], multiple studies had been tried to develop clinical results of patency by improving ECs connection. In
the same time, in scaffold-based blood vessel engineering, bioreactors, and pulsatile flow systems, planned by numerous
researchers, some important development has been established looking at the mechanical findings of the engineered blood
vessels by enhancing the settling and reformation of ECM and also completion and demarcation of “self-assembled microtissues” [97–100].
Despite numerous in vitro and in vivo results obtained by different research groups in the production of bioengineered
blood vessels, to the best of our knowledge, there are no clinical applications of any of these devices. However, Zhu et al.
[101] developed a three-dimensional scaffold for vascular tissue engineering by employing hyaluronic acid (HA) and
human like collagen. A tubular structure was obtained by cross-linking the polymers with glutaraldehyde and then by freeze
drying the obtained product previously placed in a tubular mold. Authors demonstrated that the presence of HA supports
EC proliferation and preserves their efficiency. In addition, HA improves the mechanical properties of vascular hybrid
scaffold [101].
In summary, there is no prosthetic aortic wall that is identical to the native and all attempts have the aim to bring artificial graft vessel with the native aorta. Presently, xenografts/allografts or biomimetic prostheses are those closest to the
structural and functional native vessel [102].
CONCLUSIONS
AA and especially AAA affect a high percentage of the older population in industrialized countries and mortality rates
associated with rupture of AAA are high. Smoking is a predominantly relevant risk factor for AAA [103]. Further studies are required to establish the molecular types and signaling pathways implicated in the consequence of smoking on the
induction of mPGES-1 and prostaglandin E2 receptor 4 (EP4) expression in human AAA [104].
Numerous pathophysiological procedures of aortic valve stenosis and AAs, such as macromolecule transport, gene
expression modifications, cell death pathways, calcification, inflammation, and neoangiogenesis, are directly based on
biomechanical factors [2] (Fig. 2.9). The team of Aparicio et al. [105] tried to realize a sophisticated fluid-solid growth
computational framework for modeling aneurysm evolution. Further, they illustrated the use of this novel fluid-solid growth
framework to model abdominal AA (AAA) development and to observe how the effect of the definition of the wall shear
stress (WSS) homeostatic threshold manipulates AAA progression. They concluded that enhanced understanding and modeling of the endothelial heterogeneity is important for modeling aneurysm development and, more generally, other vascular
diseases where hemodynamic stimuli play a significant role [105].
Currently, the surgical treatment is the only alternative afforded in patients with large AAA, in specific conditions.
Higher attention on the rising role of ECs in AAA pathology may be a factor in creating new curative alternative in a disease
with no corrected employed pharmaceutical treatment [9].
Nonetheless, restoration and mostly the prevention of aorta aneurysm development comprise the delay of endothelial
dysfunction with angiotensin converting enzyme inhibitors, statins, antiplatelet medications, and anticoagulants, of reactive
oxygen species and reactive nitrogen species produced by ECM, and decreasing of proinflammatory cytokines and MMPs
caused by leucocytes activity [1].
36 PART | I Overview
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FIGURE 2.9 (A) Circumferential and longitudinal stresses are the dominating principal stresses in the aortic wall. (B) Wall shear stress as a consequence
of blood flow over the endothelial layer. From Bäck M, Gasser TC, Michel JB, Caligiuri G. Biomechanical factors in the biology of aortic wall and aortic
valve diseases. Cardiovasc Res July 15, 2013;99(2):232–41. It is an open access article.
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Chapter 3
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Histology of Aortic Disease and
Progression of Aortic Dissection From
Acute to Chronic
Mohammad A. Zafar, Sven Peterss, Bulat A. Ziganshin, John A. Elefteriades
Aortic Institute at Yale-New Haven Hospital, Yale University School of Medicine, New Haven, CT, United States
Chapter Outline
Introduction 41
Normal Histology of the Aorta 41
Histology of Aortic Aneurysm and Dissection 44
Histology of the Transition From Acute to Chronic Dissection 44
Macroscopic Changes of the Transition From Acute to Chronic
Dissection 51
Stanford Type B Dissections 51
Expansion of the Dissected Aorta 51
Progression of the Dissection 55
False Lumen Patency 55
Intimal Flap Architecture and Its Dynamics 55
Stanford Type A Dissection 57
False Lumen Patency 57
References 58
INTRODUCTION
The aorta is a complex organ with an intricate intrinsic biology that transmits oxygenated blood from the left ventricle to
the systemic circulation and has sophisticated hemodynamic functions [1,2]. Aortic dissection is a catastrophic medical
condition in which separation of the medial layers of the aortic wall allows the anterograde or retrograde propagation of a
blood-filled channel within the aortic wall [1]. The incidence of aortic dissection is 3–6 per 100,000 people/year [3–5] and
it is thought to be the most common cause of death related to the human aorta [1,2]. Aortic dissection is classified according to the DeBakey (based on anatomical patterns) and Stanford (based on prognosis and therapeutic consequences) classification schemes (Fig. 3.1; Table 3.1) [6]. The histological features of the aortic wall and the histopathological change
seen in dissected aortas have been known for well over half a century [7]. However, over time, dissections (especially
type B dissections) undergo dynamic histopathological and morphological changes as they transition from the acute phase
(up to 2 weeks after the onset of symptoms [8]) to the subacute phase (between 2 weeks and 3 months after the onset of
symptoms [8]) and finally into the chronic state (greater than 3 months after the onset of symptoms [8]). In this chapter,
we characterize these changes, the natural history of this transition, and the resulting clinical implications.
NORMAL HISTOLOGY OF THE AORTA
Structurally, the aorta is classified as an elastic artery and functionally as a distributing or conducting artery [9]. The wall
of the aorta is composed of three concentric layers or tunics: the intima, media, and adventitia (Fig. 3.2).
l Tunica Intima: This is the innermost, narrowest layer that consists of a simple squamous epithelium, the endothelium,
resting on a basement membrane and subendothelial connective tissue [9–11]. The endothelium is composed of a
solitary layer of polygonal, flattened, and elongated endothelial cells and is involved in important physiologic processes
[9,10]. The basement membrane consists of the basal lamina, which borders the overlying endothelium, and the reticular
lamina, which blends with the underlying connective tissue [12]. The subendothelial layer of loose connective tissue
New Approaches to Aortic Diseases from Valve to Abdominal Bifurcation. http://dx.doi.org/10.1016/B978-0-12-809979-7.00003-1
Copyright © 2018 Elsevier Inc. All rights reserved.
41
42 PART | I Overview
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FIGURE 3.1 Classification of aortic dissection. Reproduced with permission from: Braverman AC. Diseases of the Aorta. In: Mann DL, Zipes DP,
Libby P, Bonow RO, Braunwald E, editors. Braunwald’s heart disease: a textbook of cardiovascular medicine. 10th ed. 2015. p. 1 Online resource (xxvii,
1943, 3 pages).
TABLE 3.1 Classification of Aortic Dissection
DeBakey Classification
Type I Originates in the ascending aorta and extends at least to the aortic arch and often to the
descending aorta (and beyond)
Type II Originates in the ascending aorta and confined to this segment
Type III Originates in the descending aorta, usually just distal to the left subclavian artery, and
extends distally
Stanford Classification
Type A Dissections involving the ascending aorta (with or without extension into the descending
aorta)
Type B Dissections not involving the ascending aorta
Reproduced with permission from: Braverman AC. Diseases of the aorta. In: Mann DL, Zipes DP, Libby P, Bonow RO, Braunwald E, editors. Braunwald’s
heart disease: a textbook of cardiovascular medicine. 10th ed. 2015. p. 1 Online resource (Xxvii, 1943, 3 Pages).
contains collagen fibers, fibroblasts, elastic fibers, and cells that resemble smooth muscle cells called myointimal cells
[9,11]. With advancing age, increasing amounts of lipid build up in myointimal cells, eventually leading to the develop-
ment of atherosclerosis [9,11]. A layer composed of elastin, the internal elastic lamina, demarcates the tunica intima
from the tunica media.
l Tunica Media: This is the thickest and most prominent, middle layer of the aortic wall. In the aorta, especially in
the thoracic segment, it contains an abundant amount of elastic material relative to smooth muscle cells, hence the
classification as an elastic artery [9]. It has a layered structure composed of elastin, collagen, smooth muscle cells,
and ground substance. Individual elastic fibers in the media combine together extensively giving rise to elastic
lamellae. These fenestrated elastic lamellae are arranged in concentric layers and alternate with and are separated
by circumferentially arranged layers of smooth muscle cells, fine elastin fibers, and collagenous tissue [9,11].
These structural components of the media are regularly arranged such that a “lamellar unit” of the aortic media
may be defined as consisting of two parallel elastic lamellae enclosing a smooth muscle cell, collagen fibers,
fine elastic fibers, and extracellular matrix components (Fig. 3.3) [13,14]. The thoracic aortic media contains
Histology of Aortic Disease and Progression of Aortic Dissection From Acute to Chronic Chapter | 3 43
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(A)
FIGURE 3.2 Elastic artery: aorta. (A) Elastic van Gieson (low power); (B) elastic van Gieson (high power). The highly elastic nature of the aortic wall is
demonstrated in these preparations in which the elastic fibers are stained brownish-black. In micrograph (A), the three basic layers of the wall can be seen: the
narrow tunica intima I, the broad tunica media M, and the tunica adventitia A. At high magnification in (B), the tunica media is seen to consist of concentric
fenestrated sheets of elastin (stained black) separated by collagenous tissue (stained reddish-brown) and smooth muscle fibers (stained yellow). As seen in
micrograph (A), the collagenous tunica adventitia (stained reddish-brown) contains small vasa vasorum V, which also penetrate the outer half of the tunica media.
Reproduced with permission from: Young B, O’Dowd G, Woodford P. Circulatory System. In: Young B, O’Dowd G, Woodford P, editors. Wheater’s functional
histology: a text and colour atlas. 6th ed. 2014. p. 1 Online resource (ix, 433 pages).
(B)
FIGURE 3.3 The lamellar unit. Electron micrograph of a single lamellar unit in the medial layer of the aortic wall showing a VSMC lying between two
layers of elastin fibers and surrounded by ECM proteins containing microfibrils and proteoglycans. Lamellar units are intercalated by collagen bundles.
The lamellar unit represents the basic structural and functional unit of the aortic wall. ECM, extracellular matrix; VSMC, vascular smooth muscle cell.
Reproduced with permission from: El-Hamamsy I, Yacoub MH. Cellular and molecular mechanisms of thoracic aortic aneurysms. Nat Rev Cardiol
2009;6:771–86.
approximately 53–78 lamellar units [15,16], whereas the abdominal aortic media contains approximately 28 [15].
The numerous elastic lamellae allow the aorta to distend and expand (within physiologic limits, imposed by virtue
of the tensile strength conferred by collagen in the adventitia) to receive blood pushed out by the left ventricle
during systole and then recoil and rebound during diastole [10,11,17]. The aorta thus engages in a “game of catch
with the stroke volume,” cooperating with the left ventricle and maintaining, steadying, and smoothing out arterial
pressure [1,17]. An outer elastic lamina demarcates the media from the adventitia.
l Tunica Adventitia: This is the outermost layer of the aortic wall and is composed of loose connective tissue, primar-
ily collagen. It contains the nervi vasorum, lymphatics, and the vasa vasorum (“vessels of the vessel”), which are
small arteries that provide oxygen and nutrients to the wall of the aorta itself because diffusion from the lumen is
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