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

Abstract

age analysis of neointimal hyperplasia and vascular wall transformation after balloon angioplasty. Physiol Genomics 25: 286 -293, 2006. First published January 24, 2006 doi: 10.1152/physiolgenomics.00135.2005.-Neointimal hyperplasia (NIH), a result of vascular injury, is due to the migration and proliferation of smooth muscle cells through the media and internal elastic lamina leading to vascular occlusion. We used a rat model to find the genetic regions controlling NIH after endothelial denudation in two divergent inbred strains of rats. The Brown Norway (BN) and spontaneously hypertensive rat (SHR) strains have a 2.5-fold difference in injury-induced NIH. A population of 301 F2 (SHR ϫ BN) rats underwent a standard vascular injury followed by phenotyping 8 wk after injury to identify quantitative trait loci (QTL) responsible for this strain difference. Interval mapping identified two %NIH QTL on rat chromosomes 3 and 6 [logarithm of odds (LOD) scores 2.5, 2.2] and QTL for other injured vascular wall changes on rat chromosomes 3, 4, and 15 (LOD scores 2.0 -4.6). Also, QTL for control vessel media width (MW) and media area (MA) were found on chromosome 6 with LOD scores of 2.3 and 2.5, suggesting that linkage exists between these control vessel parameters and NIH production. These results represent the first genetic analysis for the identification of NIH QTL and QTL associated with the vascular injury response.quantitative trait loci; restenosis; vascular injury; inbred strains; Brown Norway rat; spontaneously hypertensive rat INTERVENTIONS IN THE CARDIOVASCULAR system such as arterial grafts, stents, and balloon angioplasties often fail because of the development of neointimal hyperplasia (NIH). There are no effective therapies to prevent or treat this complication. For example, restenosis secondary to NIH occurs in 30 -40% of patients after balloon angioplasty for coronary artery disease (27). 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).NIH is triggered by vascular endothelial cell (VEC) disruption and injury that leads to smooth muscle cell (SMC) migration to subendothelial injury sites, followed by SMC proliferation and apoptosis. Significant neointimal thickening and decreased lumen areas are seen within 2 wk after vascular injury (16, 32). 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 candidate...

Genetic Modifier Loci Linked to Intima Formation Induced by Low Flow in the Mouse Carotid

“…Carotid IMT is a complex trait that is likely controlled by a large number of environmental and genetic factors. Recent genetic analyses of intima hyperplasia in the abdominal aorta in response to balloon injury identified several QTLs in an intercross between BN and SHR rats5. Interestingly, the most significant intima hyperplasia QTL mapped to rat chr3, which is syntenic to mouse chr2.…”

“…Intima has been proposed to be the “soil” for atherosclerosis, implying an important pathophysiologic role for this tissue4. Only one genetic analysis of intima hyperplasia in animals, the aortic response to balloon injury in an intercross between BN and SHR rats, has been published5. The authors identified several QTLs with the most significant intima hyperplasia QTL mapping to rat chr3.…”

Neointimal Hyperplasia and Vasoreactivity Are Controlled by Genetic Elements on Rat Chromosome 3

“…Hereafter, these inbred strains will be referred to as SHR and BN, respectively. The previous genome scan of an F 2 (SHR x BN) population 12 and the present substitution mapping were conducted using the same SHR and BN colonies. Breeding programs were approved by the Institutional Animal Care and Use Committee and complied with the National Institutes of Health “Guide for the Care and Use of Laboratory Animals”.…”

“…Differences in NIH-injury response of the left common and external iliac artery were observed among inbred strains of rats 2 and a subsequent genome scan of a segregating F 2 (SHR X BN) population phenotyped for postinjury NIH formation and vascular wall differences identified possible NIH-related QTLs on rat chromosomes 3 and 6 (RNO3 and RNO6). 12 The current report constitutes a continuation of this project with the long-term goal to identify the gene(s) controlling vascular remodeling and restenosis after injury. We now confirm the presence of an NIH QTL on RNO3 containing the allele(s) in part responsible for controlling the strain differences in the formation of injury-induced NIH.…”

Targeted disruption of Adamts16 gene in a rat genetic model of hypertension

“…Vessels were fixed in 10% neutral buffered formalin followed by paraffin processing, embedding, and sectioning as previously described (19). Sections were de-paraffinized, stained with DRAQ5 (Biostatus Limited) and imaged.…”