A hemodynamic model for IA formation
A wide variety of factors have been associated with IA incidence, ranging from smoking to hypertension to menopausal state in women. However, the predominance of IAs at apices of arterial bifurcations and outer curves of brain arteries suggests that the unique hemodynamics of such locations is critical in IA formation. Using two hemodynamically induced aneurysm models (discussed below), our lab has found that the insult from abnormal hemodynamics does in fact play a critical role in aneurysm formation. With the ability to obtain vessel geometries using 3D angiography we are able to determine hemodynamic flow fields using CFD in vessels and match changes in hemodynamics to morphological and biochemical changes of the vessel wall. A flow chart of the steps taken to perform this co-mapping of CFD with biology is outlined below. Using such technology we have boldly proposed that high hemodynamic wall shear stress (WSS) induces IA formation via mal-adaptive vascular remodeling.
De novo bifurcation formation
In our initial studies we asked the question, what is the specific hemodynamic environment at the bifurcation apex that leads to aneurismal remodeling? In a canine model, a Y shaped bifurcation was constructed from the two straight common carotid arteries.
CFD of vascular bifurcations were superimposed on the corresponding histology and analyzed to determine under which flow characteristics wall remodeling took place. It was found that the bifurcation vessel displayed three distinct flow environments. At the bifurcation apex impinging flow created a stagnation region (I), while the adjacent downstream region had high WSS and accelerating flow, creating positive WSSG (II). Even further downstream, WSS decreased until returning to normal values, resulting in flow recovery/deceleration and a negative WSSG region (III).
After the hemodynamic shift from straight artery flow to bifurcation flow, the newly created apex at Region I showed intimal hyperplasia, new formation of the internal elastic lamina (IEL) and in some cases collagen deposition and increased fibronectin. However, in Region II, aneurysmal damage was observed: there was disruption of the IEL, loss of endothelial cells (ECs) and smooth muscle cells (SMCs), and decreased levels of proliferation and fibronectin. In the flow recovery region (Region III) there were little biological changes to the vessel wall. The length of each bar represents the relative length of the vessel over which this phenomenon occurred. The aneurysmal changes in the bifurcation occurred at Region II, where high WSS and positive WSSG were present.
Hemodynamic exacerbation in intracranial bifurcations
Having been inspired by our de novo bifurcation results we sought to create a more anatomically relevant IA model that used an existing intracranial bifurcation. We created a rabbit basilar tip (BT) aneurysm model by increasing flow to the BT via bilateral common carotid artery (CCA) ligation. The increased hemodynamic insult alone was sufficient to cause aneurysm formation at the BT bifurcation.
Following flow increase aneurysmal remodeling occurred near the apex of the BT. This damage was characterized by loss of the IEL, media thinning and bulge formation. As shown in the histological images of the BT, loss of the IEL and bulge formation progressed from 5 days out to 27 weeks.
In order to correlate the earliest vascular damage with the responsible initial hemodynamic insult, the co-mapping procedure described above was employed to spatially map WSS and WSSG distributions with the IEL loss- the earliest and most consistent marker of aneurysmal damage. Similar to our de novo bifurcation model in the dog, we found that IEL damage again segregated to an area of high WSS and positive WSSG.
Furthermore, we found that aneurismal damage continued to develop long after the initial hemodynamic insult and after the WSS had normalized. This is result is described by the figures below in which WSS in both the basilar artery (BA) and in the BT return to pre-ligation levels after 7 or 8 weeks but the aneurysmal damage (described by an aneurysm development score) continues to grow linearly with time and is at its greatest level 27 weeks after surgery.
Molecular mechanisms of Aneurysm Initiation
Given the development of these IA changes in the vessel wall, which are spatially consistent with high WSS and positive WSSG, we are interested in determining the molecular mechanism by which hemodynamics is translated to remodeling and destruction of the vessel wall. We have found that the members of the matrix metalloproteinase (MMPs) family are instrumental in the degradation and remodeling that we observe in our models. For example, as shown in the image below, there are increased levels of MMP-2 and MMP-9 (red) expressed by SMCs (green, SMC marker alpha-actin) in the peri-apical region as early as 2 days after ligation. Additionally, we are looking to the role of nitric oxide, superoxide, and other oxidative species in IA formation.
