Advanced atherosclerotic lesions in the innominate artery of the ApoE knockout mouse.

Most previous studies of atherosclerosis in hyperlipidemic mouse models have focused their investigations on lesions within the aorta or aortic sinus in young animals. None of these studies has demonstrated clinically significant advanced lesions. We previously mapped the distribution of lesions throughout the arterial tree of apolipoprotein E knockout (apoE(-/-)) mice between the ages of 24 and 60 weeks. We found that the innominate artery, a small vessel connecting the aortic arch to the right subclavian and right carotid artery, exhibits a highly consistent rate of lesion progression and develops a narrowed vessel characterized by atrophic media and perivascular inflammation. The present study reports the characteristics of advanced lesions in the innominate artery of apoE(-/-) mice aged 42 to 60 weeks. In animals aged 42 to 54 weeks, there is a very high frequency of intraplaque hemorrhage and a fibrotic conversion of necrotic zones accompanied by loss of the fibrous cap. By 60 weeks of age, the lesions are characterized by the presence of collagen-rich fibrofatty nodules often flanked by lateral xanthomas. The processes underlying these changes in the innominate artery of older apoE(-/-) mice could well be a model for the critical processes leading to the breakdown and healing of the human atherosclerotic plaque.

Salt-sensitive hypertension develops after short-term exposure to Angiotensin II.

We hypothesized that short-term exposure to angiotensin II (Ang II) could result in structural and functional changes in the kidney that would favor sodium retention and the development of sustained hypertension. To test this hypothesis, rats were exposed to pressor doses (435 ng. kg-1. min-1) of Ang II for 2 weeks. The infusion of Ang II was associated with acute hypertension, renal dysfunction, proteinuria, and focal tubulointerstitial and vascular damage. At sites of the tubulointerstitial damage, there was a reduction in peritubular capillary endothelial cell staining. By use of immunostaining, we found focal loss of endothelial nitric oxide synthase (eNOS) in the peritubular capillaries at sites of injury and a generalized reduction in eNOS in collecting ducts, thin loops of Henle, and vascular bundles in the medulla. When the Ang II infusion ended, the rats became normotensive and renal function returned toward normal. However, exposure of the rats to high salt diet (4% NaCl) resulted in the redevelopment of hypertension after 3 to 4 weeks. Rats maintained on a high salt diet with no prior exposure to Ang II and rats placed on low salt diet (0.1% NaCl) after exposure to Ang II remained normotensive. Thus, we report a new model of salt-sensitive hypertension induced by transient exposure to pressor doses of Ang II. The mechanism may relate to microvascular injury with peritubular capillary loss coupled with functional changes, such as a loss in intrarenal nitric oxide formation, that could alter the ability of the kidney to excrete a salt load.

Peripheral vascular stenosis in apolipoprotein E-deficient mice. Potential roles of lipid deposition, medial atrophy, and adventitial inflammation.

A systematic analysis of the distribution of advanced atherosclerotic lesions was undertaken in chow-fed, 9-month-old apolipoprotein (apo) E-deficient mice to identify sites amenable for study of mechanisms of formation of stenotic lesions. The arterial tree was dissected intact and included medium-sized arteries in the extremities as well as arteries of the head and neck. The most reproducible lesions were seen in the ascending aorta and in the carotid, femoral, and popliteal arteries. Casting of the vascular tree provided additional verification of the presence of lumen narrowing in the external branches of the carotid artery. Consistent with what has been observed in human atherosclerotic arteries, there was dilation in response to lesion growth and no correlation between lesion mass and lumen loss in the mouse arteries. This adaptation was especially true in the ascending aorta, where normal lumen size was maintained at atherosclerotic sites. In contrast, the external carotid arteries were stenotic in 9 of 12 animals. Here too, however, loss of lumen did not correlate with lesion mass but did correlate with adventitial inflammation and medial atrophy. Lumen narrowing also occurred most frequently at sites where extracellular cholesterol clefts were a prominent part of the lesion. These data suggest that the stenotic process in advanced atherosclerotic vessels may depend on death of medial smooth muscle cells, possibly in response to inflammatory changes in the plaque or adventitia.