Experimental cerebral aneurysms in the female heterozygous Blotchy mouse

Abstract

The Blotchy mouse is characterized by an X-linked inherited disorder of connective tissue synthesis. The susceptibility to aneurysm formation in the cerebral arteries of the circle of Willis was compared in female heterozygous 'Blotchy' and control mice subjected to unilateral carotid artery ligation either alone or associated with hypertension. Cerebral aneurysms developed only in hypertensive Blotchy mice (6/31 vs. 0/30 in hypertensive controls). Aneurysms of the aorta and its major branches occurred in normotensive mice only in the Blotchy group in which hypertension increased the incidence of mesenteric and coeliac aneurysms. A light microscopic study of interruptions of the internal elastic lamina (IIEL) showed that they developed in arteries of both Blotchy and control mice but to a greater extent in the Blotchy group where hypertension further increased their incidence. The IIEL incidence in the aortic arch varied in parallel to the occurrence of aneurysms in all the different arterial sites. Thus, in an apparently normally viable animal, the presence of a mutated gene which indirectly leads to defective elastin and collagen fibre synthesis, favours the formation of both peripheral and cerebral aneurysms. However, the development of cerebral aneurysms requires the addition of an increase in haemodynamic stress.

Figure 1

a, Cerebral aneurysm in the anterior part of the circle of Willis at the bifurcation of the olfactory and anterior artery of a hypertensive Blotchy mouse (→). mca, middle cerebral artery; oa, olfactory artery; aa, anterior artery. b-e, semithin sections, stained with toluidine blue, from cerebral arteries of hypertensive Blotchy mice; b,c: cerebral aneurysms, d,e: small early aneurysmal structures. IEL, internal elastic lamina; (→) inflammatory cells. Scale bars: a,1 mm; b and c,100 μm; d and e, 50 μm.

Figure 2

Cortical cerebral haemorrhage in the brain from a hypertensive Blotchy mouse. Scale bar: 2 mm.

Figure 3

a, Thoracic aortae from hypertensive control (C) and Blotchy (B) mice. Note in the Blotchy the large-sized aortic aneurysm in the ascending part and the ectasia of the descending part. b, Mesenteric (M) and proximal coeliac (C) aneurysms from a hypertensive Blotchy mouse. c-d, Semi-thin sections, stained with toluidine blue, of aneurysmal arteries. c, ascending thoracic aorta from hypertensive Blotchy, note extensive fragmentation of elastic lamellae. d, mesenteric aneurysm from hypertensive Blotchy, note the important intimal proliferation with elastin fibers neosynthesis (dark wavy lines). Scale bars: a,b, 2 mm; c,d, 100 μm.

Figure 4

Incidence of interruptions of the internal elastic lamina (IIEL) in 3 different aortic sites in normotensive (□ Control; Blotchy) and hypertensive ( Control; ▪ Blotchy) mice. Results are expressed as mean ± SEM. *P ≤ 0,05 vs. normotensive (NT) and hypertensve (HT) control mice.

Figure 5

Semi-thin sections, stained with toluidine blue, of arteries from hypertensive mice. a-b, ascending thoracic aorta (a) Blotchy, note the disruption of both the internal and medial elastic lamellae compared to (b) control. c-d, descending thoracic aorta from (c) a Blotchy and (d) a control mouse. e-f, abdominal aorta (e) and iliac artery (f) of Blotchy mice. Scale bars: a-b, 200 μm; c-d, 100 μm; e-f, 200 μm.