The role ofthe endothelium and its relation to hemodynamics is a prominent candidate for atherosusceptibility in regions of complex disturbed flow. Endothelium at susceptible sites in undiseased arteries express a distinct set of balances of pro-pathological and protective pathway enhancement that define the susceptible endothelial phenotype. In Project 5 we propose (a) that hypercholesterolemia (HC) will change the phenotype balance of susceptible sites in different arteries with distinct spatial and temporal footprints, and (b) in complementary in vitro studies, that hemodynamic flow characteristics are epigenetic regulators of phenotype balance. We propose unbiased genomic analyses and focused mechanistic investigations of a primary perturbed pathway, endoplasmic reticulum (ER) stress, as complementary approaches to phenotype transition in vivo and in vitro.
In Aim 1, endothelial phenotypes of 11 arterial regions will be mapped spatially and temporally during 0-6 months of HC in adult swine in an ongoing collaboration with the FDA Center for Devices and Radiological Health in Laurel, MD. Particular focus will be upon endothelial endoplasmic reticulum (ER) stress/unfolded protein response (UPR) pathways that we have very recently identified as characteristic of athero-susceptibility in normal animals in vivo. Phenotyping of small numbers of endothelial cells (EC) including those overlying developing lesions wili be conducted following laser capture microscopy, linear mRNA amplification and microarray, and immunostaining of targeted proteins identified in the transcript studies.
In Aim 2, the contributions of hemodynamic forces and lipid environment to endothelial phenotype transition will be measured in vitro in EC exposed to arterial flow waveforms. The influence of controlled flow characteristics on mRNA transcript profiles and miRNA differential expression - with special interest in miR10a/10b regulation will be investigated.
In Aim 3, focus will be directed to endothelial ERstress and UPR mechanisms at the protein level both in vivo and in vitro. The proposal addresses at the discovery and mechanistic levels how spatially-defined as a fnction of endothelium transitions from a propathological imbalance to a pathological phenotype as a function of its lipid and hemodynamic environment.
This project addresses the role of the endothelium in the initiation and progression of atherosclerosis, a disorder that causes nearly all cardiovascular diseases. The endothelium, a single layer of cells between the blood and artery wall, is believed to change its function in order for the lesions to develop. By analyzing the genes and proteins that drive the changing function of the endothelium as lesions develop, we will determine it's temporal and spatial role in atherogenesis and reveal subtle biomarker pathways for potential therapy.
|Tang, Soon Yew; Monslow, James; R Grant, Gregory et al. (2016) Cardiovascular Consequences of Prostanoid I Receptor Deletion in Microsomal Prostaglandin E Synthase-1-Deficient Hyperlipidemic Mice. Circulation 134:328-38|
|Jiang, Yi-Zhou; Manduchi, Elisabetta; Stoeckert Jr, Christian J et al. (2015) Arterial endothelial methylome: differential DNA methylation in athero-susceptible disturbed flow regions in vivo. BMC Genomics 16:506|
|Liu, Shu-Lin; Bae, Yong Ho; Yu, Christopher et al. (2015) Matrix metalloproteinase-12 is an essential mediator of acute and chronic arterial stiffening. Sci Rep 5:17189|
|Han, Jingyan; Shuvaev, Vladimir V; Davies, Peter F et al. (2015) Flow shear stress differentially regulates endothelial uptake of nanocarriers targeted to distinct epitopes of PECAM-1. J Control Release 210:39-47|
|Jiang, Yi-Zhou; Manduchi, Elisabetta; JimÃ©nez, Juan M et al. (2015) Endothelial epigenetics in biomechanical stress: disturbed flow-mediated epigenomic plasticity in vivo and in vitro. Arterioscler Thromb Vasc Biol 35:1317-26|
|Sweet, Daniel T; JimÃ©nez, Juan M; Chang, Jeremy et al. (2015) Lymph flow regulates collecting lymphatic vessel maturation in vivo. J Clin Invest 125:2995-3007|
|Hsu, Bernadette Y; Bae, Yong Ho; Mui, Keeley L et al. (2015) Apolipoprotein E3 Inhibits Rho to Regulate the Mechanosensitive Expression of Cox2. PLoS One 10:e0128974|
|Tang, Soon Yew; Monslow, James; Todd, Leslie et al. (2014) Cyclooxygenase-2 in endothelial and vascular smooth muscle cells restrains atherogenesis in hyperlipidemic mice. Circulation 129:1761-9|
|JimÃ©nez, Juan M; Prasad, Varesh; Yu, Michael D et al. (2014) Macro- and microscale variables regulate stent haemodynamics, fibrin deposition and thrombomodulin expression. J R Soc Interface 11:20131079|
|Jiang, Yi-Zhou; JimÃ©nez, Juan M; Ou, Kristy et al. (2014) Hemodynamic disturbed flow induces differential DNA methylation of endothelial Kruppel-Like Factor 4 promoter in vitro and in vivo. Circ Res 115:32-43|
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