# The Cerebral Arterial Wall in the Development and Growth of Intracranial Aneurysms
## 5 Birth: Development
### 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). Figure 2: Illustrative case of a de novo aneurysm development. A 48-year-old lady with clinical history of seizures since childhood was admitted with a transient episode of right-sided paresthesa and hemiplegia. MRI/MR-Angiography (TOF sequence) performed in 2008 was normal without vascular anomalies (**A**). Follow-up MR-Angiography (TOF sequence) performed in 2016 showed a small de novo aneurysm of the left middle cerebral artery bifurcation (colored box) measuring 2.3 mm (**B**). Cerebral DSA was performed a month later to analyze more precisely the aneurysm (colored box) (**C**,**D**). 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 metalloproteinase. 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].