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Physiological and Molecular Mechanisms Implicated in the Neural Control of Circulation

Dynamic transcriptomic response to acute hypertension in the nucleus tractus solitarius

¹Daniel Baugh Institute for Functional Genomics/Computational Biology, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania; ²Department of Electrical Engineering, University of Delaware, Newark, Delaware; and ³Department of Chemical Engineering, University of Delaware, Newark, Delaware

Submitted 29 February 2008 ; accepted in final form 22 April 2008

Baroreceptor afferents project to the cardiovascular region of the nucleus tractus solitarius (cvNTS), and their cvNTS target neurons may play a role in governing the sensitivity and operating range of the arterial baroreceptor reflex (baroreflexes). Recent studies have shown differential gene and protein expression in the cvNTS in response to changed arterial pressure. However, the extent of these responses is unknown. Therefore, we collected differential global gene expression data in a time series following acute hypertension in awake, freely moving rats. To acquire statistically significant results and place them in functional context, we overcame several quality control requirements and developed novel analytical approaches. The physiologically new findings from the study are that acute hypertension causes very extensive, time-varying gene regulatory changes, many involving neuronal function-specific genes and systems of genes. We use standard genomic analysis methods to manage the large data sets and to develop results such as heat maps to examine patterns and clusters in the gene regulation. We used the Gene Ontology categories to provide functional context. To place our findings in the context of the relevant literature, we developed two graphical representations of the networks implicated, linking receptors and channels to signaling pathways. The results point to the multivariate complexity of the response and implicate a group of receptors as candidates for mediating nucleus tractus solitarius baroreflex function in hypertension by identifying concurrent upregulation of receptor genes. We were able to make transcription factor binding predictions and record dysregulation of heart rate correlated with the transcriptional response.

gene expression; central cardiovascular regulation; ANG II AT1 receptor; phenylephrine; adaptive molecular process; baroreflex resetting