Identification of two susceptibility loci for vascular fragility in the Brown Norway rat

Harris, Eugenie L.; Stoll, Monika; Jones, Gregory Todd; Granados, Mary A.; Porteous, William K.; Rij, André M. van; Jacob, Howard J.

doi:10.1152/physiolgenomics.2001.6.3.183

Cited by 12 publications

(16 citation statements)

References 37 publications

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“…Surprisingly, the average "wave grade" of the injured BN vessels was 2 (range 0 -6), compared with only 0.6 (range 0 -3) for the injured SHR vessels (P Ͻ 0.001). Together, these results are consistent with the thinner BN vessels (see below, Tables 2 and 3), which are also more fragile than the SHR vessels (11,23), being more easily distended than the more rigid SHR vessels. Thus the BN vessels had fewer injury-induced IEL breaks.…”

Section: Resultssupporting

confidence: 84%

“…If this were the case, then the initial MA or MW of a given F 2 (SHR ϫ BN) vessel might have a direct bearing on the amount of injury transmitted to that vessel and, in turn, influence its postinjury NIH production. In support of this, the differing numbers of postinjury IEL "breaks" and "waves" between the BN and SHR parental strains also suggest that a genetic difference in vessel fragility and distensibility (11,23) may directly influence the postinjury responses of the vasculature. We are currently trying to determine whether or not these differences in postinjury vascular changes between the BN and SHR strains can be influenced by endothelial vasodilators.…”

Section: Discussionmentioning

confidence: 82%

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

Nestor

Cicila

Karol

et al. 2006

Physiological Genomics

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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...

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Section: Resultssupporting

confidence: 84%

Section: Discussionmentioning

confidence: 82%

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

Nestor

Cicila

Karol

et al. 2006

Physiological Genomics

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“…Interestingly, the vascular walls of BN rats have been reported to harbor several anomalies compared with other strains, including a high incidence of ruptures of the internal elastic lamina of large arteries and a decreased concentration of aortic elastin. 29 Moreover, internal elastic lamina ruptures have been linked to 2 QTLs on chromosomes 5 and 10 in a cross between BN and the New Zealand Genetically Hypertensive rat, 30 and the aortic elastin content has been linked to 2 QTLs on chromosome 2 and 1 QTL on chromosome 14 in a cross between BN and Louvain rats. 31 Although these 2 traits indicate that there is vascular fragility in BN rats, it is unknown whether they have an impact on PP.…”

Section: Discussionmentioning

confidence: 99%

Genetic Determinants of Systolic and Pulse Pressure in an Intercross Between Normotensive Inbred Rats

et al. 2006

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Abstract-By continuous monitoring of abdominal aortic blood pressure via telemetry in conscious rats, we have observed that systolic, diastolic, and pulse pressures of male Brown-Norway rats were all significantly lower than that of male Wistar-Kyoto rats, despite the fact that all of the values in both strains were within normotensive ranges. Further analyses performed in 166 animals from the progeny of an F2 intercross between Brown-Norway and Wistar-Kyoto rats revealed that, despite a high correlation between systolic blood pressure and diastolic blood pressure, there was no correlation between pulse pressure and diastolic blood pressure, and the value of the correlation between systolic blood pressure and pulse pressure was lower than that of systolic blood pressure with diastolic blood pressure. Two major and highly significant (PϽ0.001) quantitative trait loci linked to pulse pressure were found on chromosome 4 (Pp1) and 16 (Pp2). Only suggestive quantitative trait loci were found for systolic blood pressure, but the strongest one (Sbp1) had the same peak and linkage probability profile as Pp1. Altogether, these data show that genetic determinants affecting pulse pressure in normotensive animals are either stronger or independent from the ones affecting systolic blood pressure and are of interest in light of evidence showing that pulse pressure is highly heritable in humans and that elevated pulse pressure is a predictor of cardiovascular risk. Key Words: blood pressure/analysis Ⅲ blood pressure/genetics Ⅲ quantitative trait loci/genetics Ⅲ rats inbred bn/genetics Ⅲ models Ⅲ animal/genetics Ⅲ vascular diseases/ultrastructure N umerous studies have used crosses between inbred rat strains to dissect out quantitative trait loci (QTLs) linked to blood pressure. Although such crosses (maintained under different environmental conditions) have made it possible to identify up to now Ϸ273 QTLs linked to blood pressure (http://rgd.mcw. edu), most of these studies (if not all) have used crosses where one of the two parental strain was hypertensive. Moreover, the majority of these QTLs concern only systolic blood pressure (SBP), because only a limited number of studies have measured blood pressure via intra-arterial devices. 1-4 Such recordings are a requirement to measure diastolic blood pressure (DBP) and pulse pressure (PP). PP is of particular interest, because it is governed, in addition to the force of ventricular ejection, by intrinsic properties of the vascular tree. The principal vascular characteristics that influence PP are the cushioning capacity of large arteries and the timing and intensity of wave reflections, 5 both of which are governed predominantly by large artery stiffness. 6 Moreover, PP is a powerful and independent predictor of cardiovascular risk, particularly in older patients, 7-10 and, thus, carries predictive information above and beyond that carried by SBP or DBP. Likewise, PP or surrogate measurements are markers of atherosclerosis, 11-13 and elevated PP associates with low renal function...

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“…Excluding the BN rat, a significant but weak negative correlation was observed in the six other strains between aortic elastin content or elastin-to-collagen ratio and IEL rupture, suggesting that the aortic elastin deficit is, at the most, a minor contributory factor that may be permissive, but it certainly does not explain the very high levels of IEL rupture in the BN rat. Recent studies have identified QTLs for IEL rupture on chromosomes 5 and 10 (6,8), findings that may lead to identification of candidate genes involved in this phenotype.…”

Section: Discussionmentioning

confidence: 99%

Characteristics of the aortic elastic network and related phenotypes in seven inbred rat strains

Behmoaras¹,

Osborne-Pellegrin²,

Guyader³

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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Extracellular matrix (ECM) molecules such as elastin and collagen provide mechanical support to the vessel wall and are essential for vascular function. Evidence that genetic factors influence aortic ECM composition and organization was concluded from our previous studies showing that the inbred Brown Norway (BN) rat differs significantly from the outbred Long-Evans (LE) and the inbred LOU rat with respect to both thoracic aortic elastin content and internal elastic lamina (IEL) rupture in the abdominal aorta and iliac arteries. Here, we measured aortic elastin and collagen contents as well as factors that may modulate these parameters [insulin growth factor (IGF)-I, transforming growth factor (TGF)-beta(1), and matrix metalloproteinase (MMP)-2] in seven inbred rat strains, including BN and LOU. We also investigated whether IEL ruptures occur in strains other than BN. We showed that LOU, LE, BN, and Fischer 344 (F344) rats were significantly different for aortic elastin content and elastin-to-collagen ratio, whereas LE, Lewis, WAG, and Wistar-Furth (WF) were similar for these parameters. BN and F344 had the lowest values. BN was the only strain to present numerous IEL ruptures, whereas F344, LE, and WF presented a few and the other strains presented none. In addition, IGF-I and TGF-beta(1) levels in the plasma and aorta differed significantly between strains, suggesting genetic control of their production. Because inbred rat strains provide interesting models for quantitative trait locus analysis, our results concerning elastin, collagen, IEL ruptures, and cytokines may provide a basis for the search for candidate genes involved in the control of these phenotypes.

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Identification of two susceptibility loci for vascular fragility in the Brown Norway rat

Cited by 12 publications

References 37 publications

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

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

Genetic Determinants of Systolic and Pulse Pressure in an Intercross Between Normotensive Inbred Rats

Characteristics of the aortic elastic network and related phenotypes in seven inbred rat strains

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