An important long-term goal in the approach to treating atherosclerosis and hypertension is to understand the mechanisms that regulate the structure of blood vessels; a process we will term """"""""vascular remodeling."""""""" Hypertension is a major risk factor for development of atherosclerosis (strong correlation between fatty streak formation and BP) and for clinical events (strong correlation between unstable angina, myocardial infarction, stroke and BP). Our major hypothesis is that hypertension is a major risk factor for atherosclerosis because the ability of the vessel to compensate for plaque burden (a process that requires outward vascular remodeling) is inhibited in hypertensive patients. We also suggest that impaired remodeling in hypertensives is due to 1) direct effects of elevated blood pressure, and 2) pressure-independent genes associated with essential hypertension that modulate the ability of the vessel to remodel. To gain insight into the mechanisms by which hypertension influences vascular remodeling we will selectively breed normotensive and hypertensive inbred rat strains that differ in their ability to remodel and perform a genetic analysis. Our preliminary data document significant differences in lumen diameter induced by blood flow among inbred rat strains. Our hypothesis is that among rats with genetic hypertension (e.g. SHR, SHR-SP, and Genetically Hypertensive rat of New Zealand (GH) there will be additional genetic determinants that modulate remodeling in response to physiologic stimuli such as flow. The use of genetic linkage analysis in the proposed project represents a novel approach to understanding the mechanisms that regulate vascular structure. Its advantage is that it is based on recombination probability, and requires no prior knowledge of the mechanisms to find the gene(s) that contribute to the process. We have developed and published a reproducible and quantitative model for flow-dependent vascular remodeling. Using this model to study inbred rat strains we have made the exciting preliminary observation that the remodeling abilities of Brown Norway (BN, high) and GH (low) strains differ by more than 2 standard deviations. Based on these data our major goal is to perform a BN x GH cross and total genomic scan to identify major genes that alter the ability of vessels to remodel in hypertension.
Aim 1 : Characterize the time course of flow- induced remodeling in the carotid arteries of Brown Norway rats (BN, high remodelers) and Genetically hypertensive rats (GH, low remodelers).
Aim 2 : Intercross GH and BN to obtain 200 F2 progeny that express a range of remodeling and blood pressure phenotypes.
Aim 3 : Genotype P0 and F2 rats and use interval mapping to determine the chromosomal location of the quantitative trait loci (QTL) that are responsible for flow-induced remodeling and blood pressure.
Aim 4. Create a congenic strain of GH rats containing genes associated with high remodeling ability.
Showing the most recent 10 out of 35 publications
