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Endothelial Transcriptome Remodeling in a Mouse Model of Chronic Hypertension

ABSTRACT: Aims: Hypertension poses a significant challenge to vasculature homeostasis and stands as the most common cardiovascular disease in the world. Its effects are especially profound on vasculature-lining endothelial cells that are directly exposed to the effects of excess pressure. Here, we characterize the in vivo transcriptomic response of cardiac endothelial cells to hypertension using the spontaneous hypertension mouse model BPH/2J. Methods and results: Verification of defective endothelial function in the BPH/2J hypertensive mouse strain was followed by acute isolation of cardiac endothelial cells and transcriptional profiling using RNA sequencing. Gene profiles from normotensive BPN/3J mice were compared to hypertensive animals. We observed over 3000 transcriptional differences between groups including pathways consistent with the cardiac fibrosis found in hypertensive animals. Importantly, many of the fibrosis-linked genes also differ between juvenile pre-hypertensive and adult hypertensive BPH/2J mice, suggesting that these transcriptional differences are hypertension-related. We also show that blood pressure normalization with amlodipine resulted in a subset of genes reversing their expression pattern, supporting the hypertension-dependency of altered gene expression. Yet, other transcripts were recalcitrant to therapeutic intervention illuminating the possibility that hypertension may irreversibly alter some endothelial transcriptional patterns. Conclusions: Hypertension has a profound effect on both function and transcription of endothelial cells, the latter of which was only partially restored with normalization of blood pressure. This study represents one of the first to quantify how endothelial cells are reprogrammed at the molecular level in cardiovascular pathology and advances our understanding of the transcriptional events associated with endothelial dysfunction.

ORGANISM(S): Mus musculus

PROVIDER: GSE104530 | GEO | 2018/04/09

REPOSITORIES: GEO

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Project description:Hypertension is a condition with major cardiovascular and renal complications, affecting nearly a billion patients worldwide. Few validated gene targets are available for pharmacological intervention, so there is a need to identify new biological pathways regulating blood pressure and containing novel targets for treatment. The genetically hypertensive âblood pressure highâ (BPH), normotensive âblood pressure normalâ (BPN), and hypotensive "blood pressure low" (BPL) inbred mouse strains are an ideal system to study differences in gene expression patterns that may represent such biological pathways. We profiled gene expression in liver, heart, kidney, and aorta from BPH, BPN, and BPL mice and determined which biological processes are enriched in observed organ-specific gene signatures. As a result, we identified multiple biological pathways linked to blood pressure phenotype that could serve as a source of candidate genes causal for hypertension. In order to distinguish causal genes from responsive genes in the kidney gene signature we integrated phenotype associated genes into Genetic Bayesian networks, identifying several novel candidate genes causal for hypertension. The integration of data from gene expression profiling and genetics networks is a valuable approach to identify novel potential targets for the pharmacological treatment of hypertension. Animals: BPH/2J, BPL/1J and BPN/3J (142 Â± 5 mmHg, 69 Â± 1.7 mmHg, 94 Â± 6 mmHg, SBP respectively) male mice (Jackson Laboratory) were maintained on a 12:12-h light-dark cycle and fed with standard chow ad libitum in facilities accredited by the Association for Assessment and Accreditation of Laboratory Animal Care. All procedures were in conformance with the National Research Council's Guide for the Care and Use of Laboratory Animals. Tissue collection: Mice (12 weeks old) were euthanized with CO2. Liver, heart, and kidney were flash frozen in liquid nitrogen. Aorta from the aortic root to the left renal artery was rinsed with PBS, immersed in 300ul of RNeasy Lysis buffer (Qiagen), and flash frozen in liquid nitrogen. RNA preparation: Tissues (~100mg, 5 mice per strain) were collected independently and homogenized in 2ml of Trizol (Invitrogen). After extraction with 0.4 ml of chloroform, RNA was extracted with SV Total RNA extraction kit (Promega) followed by DNase I treatment and purification using the RNeasy Kit (Qiagen). RNA was assayed for quality (Agilent Bioanalyzer) and yield (Ribogreen). Kidney, heart and liver RNA was amplified and labeled using a custom automated version of the RT/IVT protocol and reagents provided by Affymetrix. Aorta RNA was amplified and labeled using a custom automated version of the NuGEN Ovation WB protocol (NuGEN). Hybridization, labeling and scanning were according to Affymetrix. All samples were processed independently. Microarray analysis: Merck/Affymetrix mouse 1.0 custom arrays monitoring 38384 individual transcripts (25846 Entrez genes) were used. Raw intensity was normalized using the RMA algorithm.

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Endothelial Transcriptome Remodeling in a Mouse Model of Chronic Hypertension

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