New Research Gives Insight into Biological Mechanisms Involved in Cerebral Aneurysms
14 Sep, 2007 01:02 pm
Research using single gene knockout mice has led to a finding which confirms the importance of nitric oxide biochemistry in the formation of cerebral aneurysms. This is the first study which has directly demonstrated that genetically controlled defects in nitric oxide metabolism can promote the formation of cerebral aneurysms.
Cerebral aneurysms represent a diverse collection of vascular lesions which share as a group certain pathological features and patterns of clinical behavior. Broadly speaking, aneurysms are focal lesions of vessel wall structure which manifest as mechanically incompetent dilatations, characterized by mural deficiency of the critical elements responsible for maintenance of integrity. Aneurysms may have a wide range of hemodynamic load tolerances that partially determine the dynamic probability of rupture, and this is reflected by clinical experience which tells us that many cerebral aneurysms are asymptomatic and never rupture over the course of an affected individual’s lifetime. Most aneurysms are likely acquired through a degenerative process involving mechanical fatigue failure of the extra-cellular matrix, and related biological responses including inflammation and adaptive remodeling. Excluding unusual lesions that develop as a direct result of trauma, infection, dissection, tumor invasion and vasculitis, 3 leading mechanistic theories have emerged to explain the etiology of cerebral aneurysms: Degenerative, Immunoinflammatory and adaptive remodeling theories.
Degenerative Theory proposes that intracranial aneurysms form through cumulative wear and tear resulting from wall tension forces. This occurs spontaneously to some degree in all individuals and can be accelerated by intrinsic factors that determine vessel wall strength or extrinisic factors that determine mechanical stresses, such as hypertension. Constituitive factors that predispose to aneurysm formation can be genetically determined as in the case of Ehlers Danlos Syndrome, or they can be acquired as in cigarette smoking and atherosclerosis. Since blood vessels are living organs with the capacity for self-repair, the rate of aneurysm formation can be conceptualized as the difference between the rate of vessel wall damage and the rate of wall repair. The rate of wall damage can be further described by the expression: k(intensity of hemodynamic stress)(duration of hemodynamic stress)/(intrinsic wall strength).
Immuno-inflammatory theory suggests that aneurysms form because pathological arterial wall inflammation results in proteolysis of the extra-cellular matrix, leading to mechanical failure of the arterial wall. The nature of the immuno-inflammatory process may vary within and between individuals. Oxidative stress, infection and auto-immunity have all been implicated.
Adaptive remodeling theory proposes that aneurysms are the product of a genetically programmed biological response designed to restore homeostatic levels of shear stress. Adaptive remodeling theory tells us that living cells in the vessel wall respond to non-preferred states of shear stress by actively revising vessel wall structure in a way that would be expected to restore the preferred state of shear stress. In the case of aneurysm formation, this process might involve active degradation and replacement of existing connective tissue fibers with longer ones leading to dilatation. In this theory, the aneurysm may be viewed as a product of the adaptive response. The magnitude or rate of the adaptive response relative to the local stress field and tissue integrity may determine dynamic behavior of the aneurysm over time, and whether stabilization or rupture results.
The 3 mechanistic theories of aneurysm formation are not mutually exclusive and some interactive combination of degeneration, remodeling and inflammation are likely responsible for aneurysm pathogenesis in most individuals. Research on the basic biology of cerebral aneurysms, using single gene knockout mice, may one day lead to the development of models that explain how and why aneurysms form, and what makes some aneurysms stabilize while others go on to rupture and hemorrhage. Understanding the biology of cerebral aneurysms may eventually enable the development of drugs that will arrest the formation of cerebral aneurysms and stabilize existing aneurysms to prevent rupture in individuals who are at risk. Systemic administration of drugs can be used to achieve a global effect on the cerebral circulation. Alternatively, advances in the development of drug eluting endovascular device implants may enable a local concentrated effect in specific cerebral blood vessels that are disproportionately affected.
Abruzzo T., et al, Cerebral Aneurysm Formation in Nitric Oxide Synthase-3 Knockout Mice, Current Neurovascular Research, Vol 4, Number 3, August 2007