# The Cerebral Arterial Wall in the Development and Growth of Intracranial Aneurysms
## 6 Growth: Modification
### 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 [PERSON] 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 aneurysm 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, [PERSON] 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-mediateddegradation 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 aneurys 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 aneurys remodeling under high WSS conditions. These two different mechanisms can even coexist both longitudinally and cross-sectionally [62].