Strain Differences in Neointimal Hyperplasia in the Rat

Abstract

Abstract-We performed an initial screen of 11 rat strains by use of a standard balloon injury to the left iliac artery to observe whether genetically determined differences existed in the development of neointimal hyperplasia. Neointimal hyperplasia was assayed 8 weeks after the vascular injury on coded microscopic sections. Statistically significant differences in the percentages of the vascular wall cross-sectional areas composed of intima (percentage intima) secondary to neointimal hyperplasia were noted among the different rat strains (PϽ0.02), with the Brown-Norway (BN), Dark Agouti, and Milan normotensive strain rats having the highest and the spontaneously hypertensive rats (SHR) having the lowest percentages of intima. In a separate experiment, F 1 hybrids of SHRϫBN strains and parental BN and SHR underwent the vascular injury, and the parental strains again showed a statistically significant difference from one another in the mean percentage of intima (PϽ0.0001). The F 1 hybrids showed an average percentage of intima intermediate between those of the parental strains. The average lumen size of the injured BN vessels were significantly smaller than that of the noninjured control vessels (Pϭ0.044), but this significance disappeared when the circular areas of these vessels were calculated without taking neointimal growth into consideration (Pϭ0.649). These results provide the groundwork for a genetic linkage analysis to identify the genes that influence the development of neointimal hyperplasia after vascular injury. (Circ Res. 1999;84:1252-1257.)

Linkage analysis of neointimal hyperplasia and vascular wall transformation after balloon angioplasty

“…Inbred SHR and BN rats were obtained from Harlan Sprague-Dawley (Indianapolis, IN) and were maintained in the Division of Laboratory Animal Medicine at the Medical University of Ohio, where the genetic crosses were bred. Our previous experiments suggested that the alleles responsible for NIH growth were inherited in a codominant manner (1), and thus we selected an F 2 (SHR ϫ BN) intercross population for the genome scan. Female SHR and male BN rats were intercrossed to produce F 1 (SHR ϫ BN) progeny that were then used to breed an F 2 (SHR ϫ BN) population of 301 males.…”

“…Drug-eluting stents reduce the occurrence of short-term NIH to 20 -30%, but the long-term efficacy of these devices is not known (27). NIH is also associated with the development of significant restenosis in 20% of patients undergoing carotid endarterectomy (1) and is a major contributor to graft failure in coronary and peripheral arteries (24).…”

“…However, vascular occlusion can continue after 2 wk as SMC size increases (16,32) and proteoglycan matrix deposits continue to thicken the neointima (8,28,36,37,45). Many factors are involved in, and possibly responsible for, genetically determined variations in the NIH injury response between different strains of animals and among individual patients (1). We postulate that heritable variations in the genes for these vascular injury response elements are possible candidates for the quantitative trait loci (QTL) governing the differences in postinjury NIH among different individuals and animal strains.…”

“…We utilized a rat model for NIH formation after vascular injury to genetically dissect this complex biological process (1). In this model, we create a vascular injury by denuding the VECs of the vessel wall, similar to injury occurring in human vessels after cardiovascular interventions.…”

“…In this model, we create a vascular injury by denuding the VECs of the vessel wall, similar to injury occurring in human vessels after cardiovascular interventions. The objective of the present work was to identify chromosomal regions containing the gene(s) responsible for the differences in NIH formation after vascular injury, previously observed between inbred spontaneously hypertensive rat (SHR) and Brown Norway (BN) rat strains (1). We performed a genome scan on a segregating population of 301 F 2 (SHR ϫ BN) rats that identified multiple QTL for postinjury NIH and other vascular wall phenotypes.…”