The Cerebral Arterial Wall in the Development and Growth of Intracranial Aneurysms

Abstract

A considerable number of people harbor intracranial aneurysms (IA), which is a focal or segmental disease of the arterial wall. The pathophysiologic mechanisms of IAs formation, growth, and rupture are complex. The mechanism also differs with respect to the type of aneurysm. In broad aspects, aneurysms may be considered a disease of the vessel wall. In addition to the classic risk factors and the genetic/environmental conditions, altered structural and pathologic events along with the interaction of the surrounding environment and luminal flow dynamics contribute to the aneurysm’s development and growth. In this review, we have tried to simplify the complex interaction of a multitude of events in relation to vessel wall in the formation and growth of IAs.

1. Introduction

Intracranial aneurysms (IAs) are reported in around 3–5% of the general population and are most common in individuals aged between their third and sixth decades of life [1,2,3,4]. The mean age of rupture is between 50–55 years, with some geographic and racial differences [1,2,3,4,5,6]. The prevalence is higher in females due to hormonal status [3,6]. With the advances in imaging modalities, the rate of detecting unruptured intracranial aneurysms is also increasing globally, but the average five-year rupture risk is as low as 0.3–15% [7,8,9,10]. Several scales, including the PHASES score and ISUIA scale, may provide the cumulative risk of rupture of IAs depending on age, race, comorbidity, previous history, and size and location of the aneurysm [11,12].

IAs are pathologically characterized by a focal or segmental alteration of the arterial wall [13,14]. The loss of internal elastic lamina with disruption of the media is the classic pathologic change observed with IAs [13,14]. Precisely, IAs may be considered as the phenotypic expression of the arterial wall disease, either focal or segmental or of any underlying etiology. Considering the aneurysm just as an outward expansion of the arterial wall would not explain the different etiology of aneurysm formation and growth. The basic pathogenic mechanism of such an alteration in the arterial wall is complex and still not clearly understood. The observations made by Shievink in 1997 that the intracranial arteries have a thin tunica media and lack external elastic lamina are not incorrect but do not fit for all types of aneurysms [15]. Moreover, a series of studies have demonstrated that hemodynamic stress induces endothelial dysfunction and activates cascades of inflammatory cytokines, which amplifies a chronic inflammatory process [1].

In general, the interaction between vessel wall alteration, inflammation, hormones, genetics, hemodynamics, and environmental factors orchestrates aneurysm formation, growth, and rupture. In this review, we focused on the role of the cerebral arterial wall in aneurysm formation and growth mechanisms.

2. Methods

A meticulous search in electronic database of PubMed and Google Scholar was performed. The keywords combined for search were “Cerebral wall”; “Aneurysm”, “Development”, and “Growth” that extracted 1216 papers. Adding “Arterial wall”, “Cerebral arteries”, and “Aneurysm” we selected 655 papers. Finally, around 300 papers were considered relevant to our subject of interest. Among them, 133 papers were meticulously screened for writing this review.

3. Cerebral Arterial Wall Anatomy

The cerebral arterial wall represents the host of IAs and is the substrate of their birth and development. The wall is made up of several interconnected layers that have unique characteristics with different compositions and specific functions, such as interacting with the perivascular environment.

The inner layer of cerebral arteries is the tunica intima, which is composed of a single layer of endothelial cells directly connected to the internal elastic lamina (IEL). The next layer is the tunica media, which is predominantly composed of smooth muscle cells with some elastin and collagen fibers. The outermost layer is the tunica adventitia, which is mostly made of collagen fibers, fibroblasts, and associated cells, such as perivascular nerves, particularly in large and small pial arteries [16]. Moreover, in comparison to the systemic arteries, cerebral ones have fewer elastic fibers (muscular type) and a thinner adventitia, but they have a well-developed IEL. They do not have an external elastic lamina nor a vasa vasorum [16]. The perivascular environment of the arterial wall is made up of blood cells flowing within its lumen and cerebrospinal fluid together with the glymphatic system along the subarachnoid space. The arterial wall is in continuous connection with these elements through the modulators of the arterial wall activity and reactions, different signaling pathways, and carriers of systemic molecules, inflammatory proteins, and cytokines [17].

3.1. Tunica Intima and Endothelium

The intimal layer has an estimated total length of 20 m² [18]. The prime role of the intima is to moderate coagulation through the vessel-blood interface and regulation of biochemical cascades (i.e., the complement cascade) with hundreds of receptors involved in platelet adhesion. The tight junctions between endothelial cells of the intima not only form a cell-cell adhesion structure for the blood-brain barrier but they integrate various signaling pathways, impacting upon processes such as cell-cell adhesion, cytoskeletal rearrangement, and transcriptional control [19]. Other remarkable functions of intima are the vascular repair properties and the trans-mural diffusion of the nutrients from the blood flow in the lumen to the tissues.

3.2. Internal Elastic Lamina (IEL)

Based on the high density of elastic fibers and collagen, the major function of IEL is to regulate the distribution of pulse waves and moderate the resistance of blood pressure along the vessels. It has been shown that in conditions of complete integrity of the IEL, it may tolerate a pressure of up to 600 mmHg. However, IELs have no ability to re-attach if torn or disrupted by hemodynamic stress or forced friction. In such conditions, the only repair mechanism is observed through the intima, which can reinforce the arterial wall [20]. Mitzutani et al. have observed the differences in the pathological specimens of acute and chronic dissected intracranial [21]. While in the acute stage there is only a fragile wall, the chronic specimen nicely depicts the repair process with the formation of a new intimal layer. Therefore, the neo-intimal formation and thickening represent merely an adaptive response to reinforce the disruptive defects of the internal elastic lamina after experimental stretch injury, and this process seems to be completed between 1 and 3 months [22].

3.3. Tunica Media

The classic role of the tunica media is the regulation of vascular tone through its numerous smooth muscle cells and extracellular matrix of elastin and collagen fibers [23]. The number of smooth muscle cell layers varies with arterial size and species, with large arteries (such as the internal carotid artery) having up to 20 layers, whereas smaller pial arteries account for two to three layers, and penetrating and parenchymal arterioles have only one layer [24]. Furthermore, smooth muscle cells in the medial layer of cerebral arteries and arterioles are circularly organized and orientated perpendicular to blood flow, which helps in exerting the Bayliss effect. Indeed, Bayliss reported about 100 years ago that the smooth muscles respond to the pressure load exerted on their walls, which is actually an intrinsic property of smooth muscle cells. This response is more prominent in the cerebral arteries [24].

3.4. Adventitia and Vasa Vasorum

The tunica adventitia is the most external layer consisting of connective tissue, fibroblasts, and vasa vasorum, and is thinner than in extracranial arteries. Its main function is to provide structural support and protection to the artery. Being the outermost layer, it has properties of communication with the surrounding environment through the different signaling pathways along with the pericytes to carry out its self-regulating functions [25]. The vasa vasorum that cross the tunica adventitia are a network of microvasculature made up of arteries, capillaries, and veins with nutritive and drainage functions, transporting oxygen and removing metabolic waste from the arterial vessel walls. It is widely demonstrated that vasa vasorum can play a passive role in the pathogenesis of atherosclerosis, aneurysm, and vasculitis linked to the transport of several inflammatory mediators [26].

Adventitial vasa vasorum in coronary and carotid arteries may contribute to atherosclerotic plaque susceptibility [27]. On the other hand, the ability of cerebral arteries to obtain substances from the surrounding cerebrospinal fluid could explain why vasa vasorum in brain arteries is very rare [28]. Zheng et al., in a postmortem study, discovered a higher incidence of progressive atherosclerotic lesions in V4 segments, with a larger plaque burden and severe luminal stenosis in artery wall specimens rich in the vasa vasorum network [29]. They postulated that the adventitial neo-vascular network acts as a conduit for inflammatory cells and mediators into the plaque, aggravating the atherosclerosis pathology, and they also noted that cerebral arteries containing vasa vasorum had higher rates of atherosclerotic plaques and bleeding [29].

The depth of the vasa vasorum penetration into the tunica media depends on the thickness and number of its muscular layers [30]. Repeated bleeding from the vasa vasorum is thought to build different layers of intramural hematoma, which are then gradually reabsorbed. This causes a wall inflammation and the release of growth factors, which leads to vessel wall proliferation and weakening, though allowing aneurysm growth [31].

Vasa vasorum has been reported, especially in large saccular, giant, and fusiform aneurysms, and they have been observed with modern neuroimaging, leading to the identification and characterization of intracranial vasculopathies such as atherosclerosis, aneurysms, dissections, and vasculitis that would not be possible with standard angiography [30].

4. Different Locations

The development of a cerebral aneurysm also depends on its location in the intracranial arterial circulation. The brain arterial bifurcations represent a weak point for the birth and development of brain aneurysms because of the fenestrations of IEL and the loss of the medial layer at this point [13,14]. Saccular aneurysms are more likely to occur near the bifurcation points of the major human cerebral arteries due to the discontinuity of the media at the apex of cerebral artery bifurcations, known as a medial defect, medial gap, or raphe (Figure 1) [32].

Through autopsy studies, Canham et al. showed a discontinuity of tunica media at the apex of all bifurcations of the vessels as well as at the junction regions of brain arteries. The absence of smooth muscle cells could be related to the unique geometry and cellular response to local wall pressures [32]. The presence of this defect could be due to the circumferential orientation of the media, which would make it impossible to hold a continuous layer through the apex of the division, especially for steeply angled branches. Although medial gaps occur in both animals and humans, they are particularly prevalent in the human cerebral circulation, and they must be considered when contemplating the vascular remodeling that leads to aneurysm formation [32].

Furthermore, in comparison to the anterior circulation arteries, the posterior circulation arteries present more concentric intimal thickening, more elastin loss, and an increase in IEL proportion, indicating outward remodeling with a higher risk of fragility [33]. Moreover, the concentration of elastic fibers in the internal elastic lamina is higher in the basilar arteries and moderate in the middle cerebral arteries [34].

5. Birth: Development

5.1. Anatomic and Mechanical Factors

Blood flow within the vascular system can be either laminar or turbulent depending on the velocity and geometric conditions. Laminar flow is mainly found in large diameter vertical vessels while turbulent flow is in small and curved vessels [35]. Under turbulent conditions, the mechanical force of blood flow velocity is relatively high and, given the complex cerebral arterial geometric parameters, the stretch on the endothelial wall deregulates endothelial function [36,37]. Thus, aneurysms develop mostly at branching points with high intravascular turbulence and abnormal vessel wall shear stress. Complex vascular geometry at these points potentiates the abnormal shear stress. This is why the locations of aneurysm formation are quite constant, with 90% in the anterior circulation and mostly around the circle of Willis [38].

5.2. Genetic Factors

A familial predisposition to intracranial aneurysms suggests a strong influence of genetic factors in the development of such aneurysms. Linkage studies have identified at least five susceptible loci (1p34.3–36.13, 4q32, 7q11, 19q13, and Xp22), which were replicable across different studies. Several meta-analyses have also examined the candidate genes involved in endothelial function and vessel wall remodeling. A few risk loci (8q11, 9p21, 4q31.23, 12q22, 20p12, 2q33, and 7q13) were found to be consistent in a meta-analysis of all the major genome-wide association studies involving large cohorts [39]. On the other hand, expression profiling studies have revealed the genes involved in cell proliferation, adhesion, migration, extracellular matrix interaction, and overall inflammatory and pathogenic response in aneurysm development [39].

Moreover, connective tissue disorders such as autosomal dominant polycystic kidney disease, neurofibromatosis type-I, Ehlers–Danlos syndrome, Marfan syndrome, hereditary hemorrhagic telangiectasia, and endocrine neoplasia type-I also increase the risk of intracranial aneurysm development [40].

5.3. Structural Damage and Inflammatory Response

The fibrous proteins elastin and collagen, which are important components of the IEL and intima, provide the arterial wall its strength [41]. The main cause of remodeling, degeneration, and loss of IEL in the arterial wall is thought to be hemodynamic stress [42]. One of the reasons linked to IEL tearing is the vibration of the vessel wall generated by the arterial flow. As a direct physiological response to hemodynamic stress, the intima thickens, depositing more collagen fibers [43]. At the same time, always secondarily to the hemodynamic stress, the activity of elastase and collagenase increases and leads to IEL tearing [44]. This adaptive intimal thickening seems to compensate for the damaged IEL’s weakening of the artery wall and leads frequently to a progressive restriction of the lumen of atherosclerotic arteries [45].

Irreversible damage to IEL and collagenous intima may provide a pathological basis for the formation of aneurysms, both with the loss of equilibrium of factors contrasting hemodynamic stress and promoting controlled adaptive intima thickening. Inflammation, infection, trauma, and congenital factors that weaken the structure of the IEL may all play a role in the etiology of fusiform and dissecting aneurysms [42] (Figure 2).

The loss of vascular elasticity due to the damage of the IEL is a critical event in the development of saccular intracranial aneurysms. This is more common in patients who are susceptible to aneurysm formation. When the IEL ruptures, vascular smooth muscle cells begin to traverse the defective wall and penetrate the intima. There, they undergo hyperplasia as an adaptive response to structural damage [46]. In addition, with the torn IEL, there is endothelial apoptosis that has also been linked to the exposure of sub-endothelial collagen. Disorganization of smooth muscle cells, as well as widespread replacement of the normal wall with a hyaline-like matrix rich in collagen type-I in the medial layer and enhanced distension of collagenous fibers in the adventitial layer, have all been linked to aneurysm formation. Furthermore, aneurysms with endothelial apoptosis and medial smooth-like cell disarray or loss have drastically degraded the arterial architecture, making it more likely to burst [46].

Those changes lead to the activation of a biological cascade that involves disorganization of the tunica media with a switch of smooth muscular cells from a contractile to a pro-inflammatory/pro-extracellular matrix (ECM) remodeling phenotype. This process is boosted by an inflammatory response that includes an influx of inflammatory cells (macrophages, mast cells, neutrophils, lymphocytes T) and growing levels of cytokines (e.g., TNF, monocyte chemo-attractant protein-1, IL-1, NF-B) and matrix metalloproteinases. The mechanical load and tensile stress exceed the focally weakened artery wall, leading to the creation of an aneurysmal dome, which is mostly made up of a modified ECM rich in collagen with some smooth muscular cells, a few inflammatory cells, and a missing or discontinuous layer of endothelial cells. Aneurysmal wall remodeling is characterized by wall deterioration caused by smooth muscular cell apoptosis, ECM breakdown, inflammatory cell growth, and collagen deposition, which is influenced by the hemodynamic environment of the aneurysm sac, predisposing to rupture (Figure 3) [42].

6. Growth: Modification

6.1. Flow Dynamics and Aneurysm

Aneurysm dome stability, growth, or rupture is determined by this delicate altered vascular remodeling balance that takes place in the brain arterial wall through biological dynamic changes. Computational fluid dynamics (CFD) has been used by researchers to study the mechanical force on the vessel wall and understand the relationship between aneurysm formation, growth, and rupture [47,48,49]. Though CFD studies have revolutionized our understanding of different vascular pathologies, especially of atherosclerotic diseases and the hemodynamics of arterial bifurcations, controversies exist regarding aneurysm flow dynamics and subsequent growth [50]. Many in-vitro models were formed by considering only the laminar flow, but blood vessels are not just a mere collection of pipes. There is also the Circle of Willis with its branching points and angulations [51]. So, the complexity not only arises from the different geometric shapes of vessels and aneurysms, but there are also multiple interactions of the circulatory waveform with the phase shift, nonlinear dynamics, and multiple biophysical and pathologic processes [52,53,54,55].

Depending on blood flow, the following three types of stress have been identified on the vessel wall: the stress related to hydrostatic pressure, which works orthogonally; the shear stress, a frictional force acting tangentially to the vessel wall; the tensile stress, which acts circumferentially on the vessel wall [56]. Hemodynamic parameters such as wall shear stress (WSS), wall shear stress gradient (WSSG), oscillatory shear index (OSI), oscillatory velocity index (OVI), transverse WSS, aneurysm formation indicator (AFI), and gradient oscillatory number (GON) have been devised to understand the complex relationship of aneurysm dynamics [57].

6.2. Hemodynamic Influence and Natural History of Aneurysm

The flow environment within the vessel dictates aneurysm formation and growth [57]. Though the concept was devised from the early works by Ferguson et al. in the early 70’s, it is now well established that the wall shear stress (WSS) plays the prime role in the process of cerebral aneurysms remodeling and growth [58,59].

WSS acts directly on the vascular endothelium as a biological stimulator that modulates the cellular function of the endothelium. The association between high WSS and the initiation of aneurysm formation has already been demonstrated in animal model studies [60]. Blood flow induces cell-mediated physiological processes by exerting mechanical pressures on the vessel wall. Changes in flow (and thus WSS and pressure) over time cause wall remodeling, resulting in a change in aneurysm geometry, which, in turn, determines the flow that may drive additional physiological activities on the aneurysm wall [61].

Hemodynamics of both low and high WSS can drive intracranial aneurysm growth and rupture via different biologic mechanisms. Low WSS and high oscillatory shear index can trigger inflammatory-cell-mediated destructive remodeling, while high WSS and positive WSS gradient can trigger mural cell-mediated destructive remodeling [62]. In a three-way relationship between aneurysmal geometrical properties, blood arterial flow, and pathobiology of the arterial wall, the wall shear stress can regulate the balance between growth/repair and degradation/destruction processes. When this balance is stable, it results in aneurysm stability, while on the contrary, the loss of this equilibrium disrupts the balance, leading to enlargement and rupture of the aneurysm [62].

In a meta-analysis, Zhou et al. have also observed that aneurysmal bulge expansion often exposes the sac to lower WSS [63]. If flow instability increases, an inflammatory cascade starts, and the endothelium responds to low and oscillatory shear stress by becoming inflamed [64]. Endothelial cells create reactive oxygen species, enhance luminal permeability, and upregulate the surface adhesion molecules and cytokines in the vessel wall [65,66]. During aneurysm development, inflamed and leaky endothelium, in combination with a longer blood residence period, enhances leukocyte transmigration into the wall that can massively produce matrix metalloproteinases to degrade the ECM, driving intracranial aneurysm growth and rupture [67]. If a luminal thrombus forms, the inflammatory cell-mediated degradation becomes even more pronounced, trapping macrophages and neutrophils and harboring proteases, reactive oxygen species, and oxidized low-density lipoproteins, giving rise sometime to large, thick-wall, and partially thrombosed aneurysms [50,68].

On the contrary, the impinging flow may persist after bulge formation in some aneurysms, resulting in a high WSS and a positive WSS gradient in the aneurysmal sac. In intracranial aneurysms with high-curvature parent vessels, a high aneurysm angle, or a high inflow angle, inflow from the parent vessel can carry high inertia and strength on the wall [69,70,71]. Unlike the LSS, mural cells, rather than inflammatory cells, are most likely responsible for the destructive changes in the intracranial aneurysm wall in this pathway. Certainly, the high WSS environment is not conducive to leukocyte infiltration, which requires adequate blood residence time, as well as the endothelial cell responses that are commonly elicited under low WSS and oscillatory flow [50,72].

On the other hand, in high WSS, the phenotype-modulated smooth muscle cells are the source of proteolytic activities in this pathway. Smooth muscle cells may act similarly to the inflammatory cells, causing aneurysmal remodeling under high WSS conditions. These two different mechanisms can even coexist both longitudinally and cross-sectionally [62]. Both pathways can predominate at different stages of intracranial aneurysm growth and/or in different regions of the growing aneurysm, contributing to the broad spectrum of every aneurysm morphology. The dominant flow condition and the pathway promote change as the aneurysm geometry.

Usually, aneurysms have an average initial growth rate of 0.18 mm/year [73]. However, it is extremely unlikely that intracranial aneurysms grow at a constant time-independent rate. Individually, periods of almost no growth can alternate with bursts of growth and a high risk of rupture. An episode of SAH or an enlarged but stable aneurysm can result from a period of growth. Because lesion growth is observed in only one out of every four people with an aneurysm over a mean follow-up period of 6.7 years, and the periods without growth are supposed likely to be long [73].

Growth is rather more likely to be unpredictable and discontinuous, resulting in periods of growth and periods of no growth, as well as high and low rupture risks.

Giant aneurysms, on the other hand, do not have the same growth characteristics as berry aneurysms, and they do not grow from a small berry to a giant size [74]. They are discovered primarily as giants, frequently in the pediatric population, and have their own specific etiopathogenesis, development, and growth. It is commonly accepted that a brain aneurysm has episodic growth that could lead to rupture, more than constant growth.

7. Conclusions

The pathogenic mechanisms of development and the natural history of IAs are complex. The interaction of vessel walls with a multitude of factors determines the development and growth of such aneurysms. It is beyond our scope to discuss all the complex interactions along with the genetic and environmental factors. In this review, we mostly focused on the specific contribution of an aneurysm wall along with the flow dynamics in aneurysm development and growth.

Each cerebral aneurysm has to be considered unique, owing to the individual’s genetic makeup, the aneurysm’s specific flow dynamics, and a specific cascade of inflammatory and molecular changes occurring in the aneurysm wall that are linked to flow and genetics, causing some aneurysms to remain stable, others to grow linearly, and others to grow episodically with an independent variable represented by the abluminal vessel space.