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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_3644_Библиотеки_им_академика_М_И_Перельмана
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The younger the child,the more dynamic and interrelated the developing
organs and functions, and the more compliant and adaptable the child is
as well. Looking at diseases as fixed targets requiring mechanical correction ignores the dynamic nature of the morphological growth of the perinatal phase. The risk is to overcorrect a situation. Interdependence
between systems should be corrected to relieve the bulk of abnormal signals, allowing for spontaneous repair. Partial targeted embolization,
staged procedures and proper timing are key issues in the management
of such diseases at that age.
In other situations, we tend to ignore the identity changes that tissues
have undergone following maturation and integration to a given environment. In this later misconception all arteries or veins are postulated to
be the same throughout the body and therefore have equal capacity to
express a genetic disorder. Experience shows that although shared by all
cells,genetic defects will express in some areas and will spare others. This
segmental vulnerability is well illustrated in diseases that affect the arterial wall.
For example, describing a distal, subpial MCA aneurysm as a „berry
aneurysm of the distal branches of the MCA“ (Peters et al. 2001) is a misnomer since this denomination is traditionally used for subarachnoid
aneurysms. The former ruptures and gives intracerebral hematoma and
the latter a subarachnoid hemorrhage. Stressing the role played by the extravascular space certainly points to the fact that the subpial environment
is significantly different from the subarachnoid environment in the generation of the aneurysm, its rupture, and the response to that rupture.
The age of the lesion (how long has aneurysm been present unruptured)
and the exact time(s) of rupture are both unknown.
Using the STA or another,easy-to-access artery for structural comparison and extrapolation is probably incorrect. It mistakenly postulates that
the arterial system is homogeneous and that vessels such as the middle
91Hemorrhagic Hereditary Telangiectasia or Rendu-Osler-Weber Disease
Scheme 2.17. Underlying steps
from genotypic to phenotypic
expression in neural crest
migration. ML, medial lateral;
CC, craniocaudal; VD,
ventrodorsal
2Introduction and General Comments Regarding Pediatric Intracranial Arteriovenous Shunts92
Scheme 2.18A. Vascular
vulnerability phenotypic
expression: continuous
variability
Scheme 2.18B. Vascular
vulnerabilityphenotypic
expression: uncertain
variability
cerebral artery (MCA) and superficial temporal artery (STA) can be compared.The segmental vulnerability will show that these vessels have significant phylogenetic, embryologic, and hemodynamic differences. The
hemodynamics and shear stresses in both systems are different,with no
diastolic flow occurring in the STA. In addition,the STA does not develop
aneurysms, which is a characteristic of the external carotid biological
evolution in comparison to the internal carotid branches. The few
aneurysms described in the superficial temporal arterial system are seen
following trauma or MCA–STA anastomoses, which introduces a diastolic flow in the external carotid artery (ECA) and subsequently in the
STA. This certainly emphasizes the role played by the environment and
that of the signals coming from a distal territory, the surrounding tissue
in the regulation and expression of the various genes. One can also question the maturation over time of some genetic programs of modeling and
remodeling of the brain vessels. The cell turnover and the repair capacities are unlikely to be continuous but rather spread over equal periods
throughout life.Postnatal maturation presents additional challenges that
one should foresee in interpreting gene expression disorders (Lasjaunias
2000).
2.8 Vascular Remodeling and the Congenital Nature
of Arteriovenous Shunts
The provocative statement made by Professor G. Yasargil in the 1980 s
regarding the possible noncongenital origin of cerebral AVM was not
fully accepted at that time,although some felt it might be correct.The role
of the endothelial cell is becoming better understood, and experience
gained in prenatal diagnosis and progressive treatment of these lesions
gives further credibility to Yasargyl’s observation and allows a general
hypothesis to be elaborated.
In what is considered the normal vascular tree, continuous remodeling
will take place. The emerging concept of vascular remodeling is as follows
(Gibbons and Dzau 1994). The vessel wall is an active, integrated organ
composed of endothelial, smooth-muscle, and fibroblast cells combined
with each other in a complex autocrine–paracrine set of interactions.The
vasculature is capable of sensing changes within its milieu, integrating
these signals by intercellular communication, and changing itself
through the local production of mediators that influence structure as well
as function. Vascular remodeling is an active process of structural alteration that involves changes in at least four cellular processes – cell
growth, cell death, cell migration, and production or degradation of
extracellular matrix – and is dependent on a dynamic interaction between locally generated growth factors,vasoactive substances,and hemodynamic stimuli. Remodeling is usually an adaptive process that occurs
in response to long-term changes in hemodynamic condition, but it may
subsequently contribute to the pathophysiology of vascular diseases and
circulatory disorders.The biological process of vascular remodeling may
be divided into the following components:(a) the detection of signals due
to changes in hemodynamic conditions and humoral factors (sensors);
93Vascular Remodeling and the Congenital Nature of Arteriovenous Shunts
(b) the relay of signals within the cell and to adjacent cells (transducers);
(c) the synthesis and release of activation of substances that influence cell
growth, death, or migration or the composition of the extracellular matrix (mediators); and (d) the resulting structural changes in the vessel
wall (both cellular and noncellular components).The endothelial surface
is constantly exposed to humoral factors, inflammatory mediators, and
physical forces.The endothelium is strategically located to serve as a sensory cell assessing hemodynamic and humoral signals,as well as an effector cell eliciting biological responses that may eventually affect the structure of the vessel.
2.8.1 Endothelium as a Sensor and Transducer of Signals
Hemodynamic stimuli involve, in essence, the vessel remodeling itself in
response to long-term changes in flow such that the luminal diameter is
reshaped to maintain a constant predetermined level of shear stress.The
capacity of the endothelium to sense shear stress is therefore an important determinant of luminal diameter and overall vessel structure
(Fig. 2.32).
In vitro, increases in shear stress alter the balance of endothelial cellderived mediators involved in the regulation of vascular tone, hemostasis, vascular-cell growth, and matrix production. New evidence suggests
that shear stress activates a genetic program that alters the balance of the
mediators of remodeling by activating the transcription of genes for factors such as nitric oxide synthase,platelet-derived growth factor (PDGF),
and transforming growth factor b1 (TGF-b1).
2Introduction and General Comments Regarding Pediatric Intracranial Arteriovenous Shunts94
Fig. 2.32. Arterial adaptations
to increased pressure and
increased blood flow.
(Berdeaux 1994, adapted
from Langille 1993)
2.8.2 Endothelium-Specific Receptor-Coupled Event
Endothelial cells regulate vascular tone, hemostasis, inflammation, lipid
metabolism, cell growth, cell migration, and interactions with the extracellular matrix through many receptor-mediated mechanisms.Similarly,
the delicate balance between thrombosis and fibrinolysis involves specific endothelial-cell receptors for proteins involved in both enzymatic
cascades.
2.8.3 Endothelium and Mediator-Effector Molecules Involved with Remodeling
Endothelial cells can participate directly in vascular remodeling by
releasing or activating substances that influence the growth, death, and
migration of cellular elements or the composition of the extracellular
matrix. The contents of vessel walls may be determined by a balance
between cell growth and programmed cell death, or apoptosis.In contrast
to cell necrosis, apoptosis is a selective process of cell loss that occurs
without evoking an inflammatory response.
2.8.4 Role of Matrix Modulators in Vascular Remodeling
The extracellular matrix is composed of the scaffolding elements of
collagens (type I, III, IV, and IV) and elastin embedded in a mixture of
glycoproteins (e.g., fibronectin) and proteoglycans (e.g., heparin sulphate).Vascular remodeling entails the reconstruction of the matrix scaffolding and therefore a process of active proteolysis and resynthesis of
these proteins.The theme of homeostatic balance is again evident in that
the proteolytic factors produced within the vasculature are counterbalanced by endogenous protease inhibitors.
Alterations in the balance of factors modulating matrix composition
appear to be important determinants of vessel architecture.
2.8.5 Clinical Implications of Vascular Remodeling
Vascular injury is induced by tissue ischemia resulting from occlusion of
the vase vasorum and mechanical injury. Studies suggest that PDGF and
TGF-b1 are involved in the neointimal proliferative response to surgical
injury.
The increased intraluminal pressure appears to result in thickening of
the vessel wall. An imbalance between endogenous growth promotors
and inhibitors may allow occlusion of vein grafts. Patients with saphenous vein grafts have impaired generation of nitric oxide by endothelial
cells and increased angiotensin-converting enzyme activity. Thus, the
adaptive response of vein grafts to surgical implantation into the arterial
circulation involves a dynamic interplay among vasoactive substances,
local growth factors, and hemodynamic stimuli.
95Clinical Implications ofVascular Remodeling
The possible closure of the ductus arteriosus can be induced either by
the increased generation of local vasoconstrictors (e.g., endothelin) in
response to increased oxygenation at the time of birth or by pharmacological blockade of endogenous vasodilators (e.g., prostacyclins by indomethacin).Hypertensive vessels in animals and in humans are characterized by a thickened media, a reduced lumen, and an increased extracellular matrix. Structural changes in hypertensive vessels are associated
with increased expression of growth factors such as TGF-b1, local
vasoactive substances such as angiotensin II, matrix proteins such as
collagen and elastin, and matrix proteinaceous such as collagenase and
elastase. These alterations predispose patients with hypertension to the
sequelae of this disorder.
Vascular remodeling also influences the natural history of atherosclerotic lesions. The endothelium appears to have a central role in this initiation of atherogenesis by regulating the infiltration of mononuclear cell
and endothelial malfunction.We postulate that vascular stenosis increases shear stress and thereby induces an increase in the vessel radius to normalize shear stress, as described above in normal vessels. If this compensatory mechanism fails to keep pace with the growth of the plaque, the
stenosis may lead to flow disturbances that further enhance the progression of the lesion and favor platelet aggregation and plaque rupture.Why
does balloon angioplasty increase the luminal diameter in the vast majority of cases? Four factors determine the characteristics of flow after
angioplasty: capacity of the regenerated endothelial surface to act as a
transducer, the relative balance between cell growth and cell death, and
the capacity of the remodeled matrix to contract and maintain the geometry of the vessel affected by the endovascular procedure. The resultant
luminal diameter will depend on the net balance between factors promoting shear stress-induced expansion of the area of the lumen and the
reparative response to injury that promotes restenosis due to the formation of neointima and matrix modulation.
With time, the remodeling results in a gradual decrease in compliance,
although it usually remains compatible with function. This results in a
progressive morphological shift in the angioarchitectural features of the
vascular anatomy. The normal endothelial cells adjacent to an AVM play
a central role in the remodeling process, and their plasticity is a key factor in understanding the natural history of an AV shunt. It has been
demonstrated that in the arterial wall proximal to an AV shunt, changes
in pressure within the vessel result in a change in wall thickness (with
release of local growth factors), while velocity changes result in lumen
enlargement (preserving the wall thickness). The concept of secondary
angiopathy related to chronic high flow (or flow changes beyond normal
equilibrium) applies to a normally reacting vasculature that has been
abnormally triggered by an AVM. This intraluminal trigger is a stress
trigger, which can be related to flow, pressure, or other factors (Schemes
2.19a–c, 2.20).
2Introduction and General Comments Regarding Pediatric Intracranial Arteriovenous Shunts96
97Clinical Implications ofVascular Remodeling
Scheme 2.19A. Constitution
of a quiescent AVM
Scheme 2.19B. Revelation
of the dormant defect into
an AVM
It may be postulated that, if triggering events were eradicated, highflow angiopathy would no longer develop or persist.This can be achieved
by controlling the AV shunt and is well demonstrated by the disappearance of flow-related arterial aneurysms following successful treatment of
a CAVM. This has served as a rationale to offer partial, targeted treatment
for certain types of AVMs. Over time, the increased rigidity and fragility
of this stressed vascular system becomes evident,when even partial and
limited attempts to remediate the abnormal shunting zone lead to failure
of the remaining normal vasculature,with early rupture and hemorrhage
or ischemia as a result of intervention.
These remarks point to the difference that should be made between
primary lesion and secondary induced changes that are not part of the
CAVM diseases, even if they represent its clinically eloquent part. Still,
CAVM, even with variable high-flow angiopathic changes, is a heterogeneous group of abnormalities. With this apparent heterogeneity, some
specific features are recognized in young children, including systemic
manifestations, hydrodynamic disorders, and severe cerebral trophic
changes. The specific morphological alterations encountered during
the course of the disease in this age group are striking, as most of them
are not observed in otherwise similar AVMs discovered in adults. If the
lesions were present during the first few years of life– the time of specific
vulnerability of the maturing brain– one would expect to find some
degree of brain damage. It has become apparent that AVMs diagnosed in
2Introduction and General Comments Regarding Pediatric Intracranial Arteriovenous Shunts98
Scheme 2.19C. Induced high-flow angiopathy
adults are not present at birth,and if their initial course is clinically silent,
the lesion was probably morphologically occult (Fig. 2.33).
The term „malformation“ means failure to comply to a molded morphology or visible shape. Adding congenital to this denomination needs
further explanation. The term „congenital“ means the period of the
development that resides in the matrix. This does not mean embryology
or genetics. Congenital in short means before birth.
If we postulate that AVMs are the result of a congenital event,although
occult, its expression will later become morphologically detectable. Its
impact is primarily structural,cellular,linked somehow to vascular modeling and remodeling.
The quiescent dysfunction that results (and persists over time) must involve the endothelial cells or any cell that interacts directly with its function (e.g., astrocytes, pial, ependymal). For this dysfunction to be eventually revealed as a morphological abnormality,a trigger factor is necessary.
We call such postulated triggers revealing triggers (Schemes 2.21, 2.22).
99Clinical Implications ofVascular Remodeling
Scheme 2.20. Different phases
necessary for the development
of cerebral arteriovenous malformation (AV M ). 1, Quiescent
cellular dysfunction; 2, triggered susceptible cell; 3, active
AV shunt developing stress
trigger (ST) on the proximal
and distal vasculature; 4,
high-flow angiopathy with
proximal arterial aneurysm,
distal venous ectasia, and
stenosis. RT, revealing trigger
2Introduction and General Comments Regarding Pediatric Intracranial Arteriovenous Shunts100
Fig. 2.33A–F. Legend see pp.102
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