Preclinical Intracranial Aneurysm Models: A Systematic Review

Intracranial aneurysms (IA) are characterized by weakened cerebral vessel walls that may lead to rupture and subarachnoid hemorrhage. The mechanisms behind their formation and progression are yet unclear and warrant preclinical studies. This systematic review aims to provide a comprehensive, systematic overview of available animal models for the study of IA pathobiology. We conducted a systematic literature search using the PubMed database to identify preclinical studies employing IA animal models. Suitable articles were selected based on predefined eligibility criteria following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Included studies were reviewed and categorized according to the experimental animal and aneurysm model. Of 4266 returned results, 3930 articles were excluded based on the title and/or abstract and further articles after screening the full text, leaving 123 studies for detailed analysis. A total of 20 different models were found in rats (nine), mice (five), rabbits (four), and dogs (two). Rat models constituted the most frequently employed intracranial experimental aneurysm model (79 studies), followed by mice (31 studies), rabbits (12 studies), and two studies in dogs. The most common techniques to induce cerebral aneurysms were surgical ligation of the common carotid artery with subsequent induction of hypertension by ligation of the renal arteries, followed by elastase-induced creation of IAs in combination with corticosterone- or angiotensin-induced hypertension. This review provides a comprehensive summary of the multitude of available IA models to study various aspects of aneurysm formation, growth, and rupture. It will serve as a useful reference for researchers by facilitating the selection of the most appropriate model and technique to answer their scientific question.

Diabetes, Incretin Therapy and Thoracic Aortic Aneurysm – What Does the Evidence Show?

Epidemiological evidence supports a reduced prevalence of Thoracic Aortic Aneurysm (TAA) and Abdominal Aortic Aneurysm (AAA) in patients with Diabetes (DM). The mechanisms underlying this negative association are unknown. Some studies support that hyperglycemia has effects on the Extracellular Matrix (ECM), resulting in collagen cross-links and altered proteolytic activity, which ultimately counteracts aneurysm formation. However, recent experimental research indicates that incretin- based anti-diabetic therapy and Glucagon-Like Peptide-1 (GLP-1) may reduce the formation of TAA. GLP-1 is a peptide hormone, released from intestinal L-cells in response to hormonal, neural and nutrient stimuli. In addition to potentiation of meal-stimulated insulin secretion, GLP-1 signaling exerts numerous pleiotropic effects on various tissues, including protective effects on the myocardium and vascular endothelium. Recent studies also report protective effects of GLP-1 based therapy on the formation of aneurysms in animal models and direct effects of GLP-1 signaling on the molecular mechanisms suggested to influence TAA formation, including inflammation, proteolytic activity and collagen composition. In this narrative review, we present the available evidence for effects of GLP-1 on experimental aneurysm development and discuss the potential role of GLP-1 in aneurysm formation based on available data from pre-clinical and clinical studies.

Temporary surgical clipping of flow-diverted arteries in an experimental aneurysm model

OBJECTIVE Surgical management of recurrent aneurysms following failed flow diversion may pose difficulties in securing vascular control with temporary clips. The authors tested the efficacy and impact of different types of aneurysm clips on flow-diverted arteries. METHODS Six wide-necked experimental aneurysms were created in canines and treated with Pipeline flow diverters. In 4 aneurysms, occlusion of the artery at the level of the proximal and distal landing zones (n = 2 per aneurysm) was attempted, using temporary, fenestrated, single, and double permanent aneurysm clips. Two aneurysms served as unclipped controls. Serial angiography was performed to investigate the efficacy of clip occlusion, flow diverter deformation, and thrombus formation. After the animals were killed, the flow-diverted aneurysm constructs were opened and photographed to determine neointimal or device damage as a result of clip placement. RESULTS Angiography-confirmed clip occlusion was only possible for 4 of 8 of the tested flow-diverted arterial segments. Clip application attempts led to filling defects consistent with thrombus formation in 2 of 4 flow-diverted constructs, and to minor damage of the flow diverter with neointimal fracture in 1 of 4 cases. CONCLUSIONS Aneurysm clips placed on canine parent arteries bearing a Pipeline flow diverter were unable to reliably stop blood flow. Application of aneurysm clips can cause mild damage to the device and neointima, which might translate into thromboembolic risks. If possible, vascular control should be sought beyond the terminal ends of the implanted device.

Abstract 304: Chemokine Receptor CCR2 Mediates Monocyte Mobilization and Migration in Experimental Aneurysms

Abdominal aortic aneurysm (AAA) is a macrophage-driven vascular inflammatory disease. Chemokine receptor CCR2, a critical mediator of monocyte mobilization and migration, promotes AAA pathogenesis in hyperlipidemic mice following angiotensin II infusion. This study examined the role o CCR2 signaling in AAA formation in a mechanistically distinct experimental aneurysm model. AAAs were created in 10 week old male CCR2 knockout (KO) and wild type C57BL/6J mice via transient intra-aortic porcine pancreatic elastase (PPE) infusion. Aneurysm progression and aortic cellularity were evaluated using ultrasonography, histology and FACS analyses. In CCR2 KO mice, minimal aneurysmal enlargement was apparent following PPE infusion. Histologically, aortic medial elastin and smooth muscle cellularity were minimally degraded, and mural macrophage accumulation and angiogenesis were also significantly reduced compared to WT mice. Significantly fewer circulating and splenic inflammatory monocytes were identified via FACS analysis in KO mice, with a reciprocal increase in bone marrow monocyte cellularity. In in vivo monocyte migration assays, CCR2 deficiency was associated with a 60 -70% reduction in migration of intravenously transferred monocytes into aneurysmal aortae. In conclusion, targeted deletion of CCR2 in mice profoundly reduces mobilization of inflammatory monocytes from the bone marrow, while suppressing aneurysmal degeneration following PPE infusion. CCR2 signaling may represent an attractive target for therapeutic inhibition in medical management of AAA disease.