Strain-Dependent Vascular Remodeling Phenotypes in Inbred Mice

Abstract

Vascular remodeling is a response of blood vessels to both physiological and pathological stimuli, leading to either vessel enlargement (positive remodeling) or reduction in vessel diameter (negative remodeling). Examples of remodeling have been observed in fetal development 1 and after graft placement 2-5 or angioplasty. 6 -8 In humans, vascular remodeling but not intimal lesion formation was shown to account for the majority of the restenosis in response to angioplasty procedures. 9,10 We have recently established and characterized a mouse model of arterial remodeling. 11 In this model, flow in the common carotid artery is interrupted by ligation of the vessel near the carotid bifurcation. Using FVB/NJ mice, this resulted in a dramatic reduction in vessel diameter and formation of an intimal lesion. Neointima formation and the influx of inflammatory cells in this model are reduced in P-selectin-deficient mice, while the reduction in vessel diameter is not affected by the lack of P-selectin. 12 Additional specific factors that mediate the remodeling response are beginning to emerge. Several studies have implicated nitric oxide (NO) as an inhibitor of remodeling events. [13][14][15][16][17] Our own studies demonstrated that alterations in blood flow also lead to changes in gene expression of platelet-derived growth factor Achain and B-chain, factors known to modulate proliferation and migration of smooth muscle cells (SMC). 18 Preliminary experiments in our laboratory indicated that there is wide qualitative and quantitative variation in the vascular remodeling response of different mouse strains. To provide the basis for a genetic analysis, we subjected 11 different strains of inbred mice to carotid artery ligation for analysis of the remodeling response. Large differences were found between strains with regards to negative as well as positive remodeling and intimal lesion formation. The magnitude of neointima formation correlated with increased loss of SMC occurring immediately after ligation of the carotid artery as well as enhanced growth properties of SMC in vitro.

Critical role of the NADPH oxidase subunit p47phox on vascular TLR expression and neointimal lesion formation in high-fat diet-induced obesity

“…17,18 Different mouse strain and genetic background have been shown to have a significant different in the neointimal formation in carotid ligation model. 45,46 Whether these factors contribute to this discrepancy in present studies remains unknown. In addition, fed ApoE KO mice with HF diet resulted in a significant atherosclerotic neointimal formation and this was accompanied by dramatic increases in p47 phox and Ang-2 expression.…”

Genetic determinants of vascular remodelling

“…Discussed here is vascular remodelling with a focus on the process of intima media thickening (IMT), an important manifestation of atherosclerosis in the carotid artery. Finally, the important contribution of genetic factors to vascular remodelling, and IMT in particular, has been confirmed as a result of recent human and animal studies (1)(2)(3)(4).…”

“…Vascular remodelling is genetically controlled in the complete occlusion model as measured in inbred mice strains (2). Specifically, significant differences in variations in vessel size, neointima formation, lumen area and medial thickness were found.…”

Regulation of smooth muscle by inducible nitric oxide synthase and NADPH oxidase in vascular proliferative diseases

“…Granted genetic variations between animal strains [62,92], the studies outlined above indicate that the benefits or drawbacks from inhibiting iNOS vary with the type of vascular injury. This is reminiscent of other pathologies in which the role of iNOS as a detrimental or beneficial protein during inflammation has been already highlighted [90].…”