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

Abstract

Neointimal Hyperplasia (NIH) can lead to restenosis after clinical vascular interventions. NIH results from complex, and poorly understood, interactions between signaling cascades in the extracellular matrix and disrupted endothelium which leads to vessel occlusion. Quantitative Trait Loci (QTLs) were previously reported on rat chromosomes 3 and 6 through linkage analysis of post-injury NIH in mid-iliac arterial sections. In the current study, substitution mapping validated the RNO3 NIH QTL but not the RNO6 NIH QTL. The SHR.BN3 congenic strain had a three-fold increase in %NIH compared to the parental SHR strain. A double congenic study of RNO3+RNO6 NIH QTL segments suggested less than additive effects of these two genomic regions. To test the hypothesis that changes in vessel dynamics account for the differences in NIH formation, we performed vascular reactivity studies in the BN, SHR, SHR.BN3 and SHR.BN6 strains. De-endothelialized left common carotid artery rings of the SHR.BN3 showed an increased vascular responsiveness when treated with serotonin or prostaglandin F2α, with significant differences in EC50 and Emax (p < 0.01) values compared to the SHR parental strain. Since both vascular reactivity and %NIH formation in the SHR.BN3 strain are significantly higher than the SHR strain, we postulate that these traits may be associated and are controlled by genetic elements on RNO3. In summary, these results confirm that the RNO3 NIH QTL carries the gene(s) contributing to post-injury NIH formation.

Dissecting the genetic components of a quantitative trait locus for blood pressure and renal pathology on rat chromosome 3

“…This overlaps with loci identified for BP in the DS [25], Fawn-Hooded hypertensive (FHH) [26] and SHR rats [27]. However, this locus is distinct from two additional BP QTLs previously identified and confirmed in DS rats [28,29].…”

Animal Models of Neointimal Hyperplasia and Restenosis

“…Sprague-Dawley and Wistar rats are frequently used strains for atherosclerosis and neointimal hyperplasia research. Rats that mimic certain aspects of cardiovascular pathophysiology, such as the spontaneously hypertensive rat ( 71 ) or the obese rat versus the lean Zucker rat [diabetes type 2 ( 72 )], can be used to study the specific influence of key cardiovascular risk factors on neointimal hyperplasia. These models, combined with angioplasty procedures (eg, stenting), allow for a more translational investigation of cellular and molecular processes of restenosis compared with mere dietary or mechanical injury models ( 73 ).…”

RNO3 QTL regulates vascular structure and arterial stiffness in the spontaneously hypertensive rat

“…Studies from our laboratory have demonstrated that heritable genetic variations encode physiological differences in vascular reactivity within the arterial wall ( 10 ). Specifically, we found increased vasoconstriction in SHR vessels compared with Brown Norway (BN) vessels in response to serotonin and prostaglandin F2α, and when the rat chromosome 3 (RNO3) alleles from the BN rat are introgressed to form the SHR.BN3 congenic strain, there is a further increase in vasoconstriction when compared with that observed in the parental SHR vessels ( 11 ). Given that increased vasoconstriction may lead to increased blood pressure, we sought to determine if the congenic SHR.BN3 strain demonstrates increased blood pressure compared with the parental SHR strain, and to further compare and characterize the relative stiffness, arterial wall structural components and extracellular matrix (ECM) of the SHR.BN3 and SHR strains using ultrasound and multiphoton microscopy (MPM).…”