Cellular and molecular mechanisms of saccular intracranial aneurysm formation and rupture

Abstract

Subarachnoid hemorrhage from ruptured saccular intracranial aneurysms (sIAs) comprises a significant clinical burden with high mortality rates. The invasive therapeutic procedures come with a risk of severe complications often equaling or exceeding the risk of sIA rupture. Therefore, the assessment of sIA rupture risk is of absolute importance. To realize this, a thorough understanding of the underlying cellular and molecular mechanisms of sIA formation and rupture is pivotal. Up to date these mechanisms remain poorly understood. A growing body of evidence from human and animal studies supports the theory that hemodynamic stress causes endothelial dysfunction which subsequently induces inflammation and remodeling in the vascular wall, thus leading to sIA formation. Ruptured sIAs are reported to have higher degrees of inflammation, mural cell death, extracellular matrix breakdown and oxidative stress compared to unruptured sIAs. This is evident on morphological, molecular and gene expression level. However, due to the complex and unknown interplay between the cellular and molecular mechanisms, together with methodological issues, reasons as to why some sIAs rupture and other do not are difficult to assess. Based on the reviewed data, it is hypothesized that the balance of inflammation and remodeling in the vessel wall induces adaptive changes leading to unruptured sIAs, while maladaptive changes result in sIAs prone to rupture.