Strain-dependent vascular remodeling phenotypes in inbred mice

Abstract

We have recently established a mouse model of arterial remodeling in which flow in the left common carotid artery of FVB mice was interrupted by ligation of the vessel near the carotid bifurcation, resulting in a dramatic reduction of the lumen as a consequence of a reduction in vessel diameter and intimal lesion formation. In the present study we applied this model to various inbred strains of mice. Wide variations in the remodeling response with regard to reduction in vessel diameter, intimal lesion formation, lumen area, and medial hypertrophy were found. On carotid artery ligation SJL/J mice revealed the most extensive inward remodeling leading to an approximate 78% decrease in lumen area while lumen narrowing in FVB/NJ mice was largely due to extensive neointima formation as a result of smooth muscle cell (SMC) proliferation. Significant positive remodeling in the contralateral right carotid artery with a >20% increase in lumen area was observed in SM/J and A/J mice. An in vitro comparison of growth properties of SMC isolated from FVB/NJ mice and a strain that exhibited very little SMC proliferation (C3H/HeJ) demonstrated accelerated growth of SMC from FVB/NJ following serum stimulation. In vivo, SMC proliferation in the FVB/NJ strain was preceded by a 37% loss of medial SMC occurring within the 2 days after ligation, however, cell death was not detectable in C3H/HeJ mice. These findings suggest that the mechanisms leading to lumen narrowing in the vascular remodeling process are genetically controlled.

Figure 1.

The response of the left common carotid artery from inbred mouse strains 4 weeks after ligation is shown. The data were normalized to the left carotid artery from unmanipulated control mice by expressing them as a ratio of ligated vessel over control vessel. Absolute values for neointima formation are also shown in C. The values reflect means ± SE. The P value is indicated for P ≤ 0.1 for comparisons between ligated and control animals.

Figure 2.

Representative photomicrographs of cross-sectioned mouse carotid arteries from FVB/NJ, C3H/HeJ, and SJL/J mice 4 weeks after ligation of the left carotid artery. The unmanipulated artery from control mice is shown on the left. Note the marked decrease in lumen area with extensive neointima formation but little inward remodeling in the FVB/NJ mice (A and B), relatively little inward remodeling with no intimal hyperplasia in C3H/HeJ mice (C and D), and extensive inward remodeling with little neointima formation in SJL/J mice (E and F). Hematoxylin-eosin stain; original magnification, ×200.

Figure 3.

The response of the contralateral right carotid artery 4 weeks after ligation of the left carotid artery is shown. The data were normalized to the right carotid artery from unmanipulated control mice by expressing them as a ratio of right carotid from the ligated animal over right carotid from control animals. The values reflect means ± SE. The P value is indicated for P ≤ 0.1 for comparisons between ligated and control animals.

Figure 4.

Growth of aortic SMC isolated from FVB/NJ and C3H/HeJ mice in response to 10% fetal calf serum. Equal numbers of cells were plated at day 0 and cell numbers were counted at the indicated time points after plating. Growth curves from two separate cell isolations (1 and 2) are shown.

Figure 5.

The number of medial SMC on cross-sectioned common carotid arteries from C3H/HeJ and FV B/NJ mice was determined 2 days after ligation of the vessel. The data are expressed as a percentage of medial SMC in the unmanipulated contralateral artery. There was a significant loss of medial SMC in FVB/NJ but not in C3H/HeJ mice. Values represent means ± SE, 5 animals per group.