A physiogenomic approach to study the regulation of blood pressure

Abstract

van der Giet. A physiogenomic approach to study the regulation of blood pressure. Physiol Genomics 23: 46 -53, 2005. First published June 7, 2005; 10.1152/physiolgenomics.00077.2005.-Several vasoregulatory systems including the renin-angiotensin system, sympathetic vasoregulation, and cytokine release have been studied extensively. The aim of the present study was to establish a physiogenomic screening model for differentially expressed genes in the regulation of blood pressure that might give a hint as to new vasoregulatory mechanisms. We induced acute hypotension in normotensive rats, assuming that vasoregulatory systems will counteract hypotension. Microarray transcriptome analysis was performed from kidneys 6 h after the induction of acute hypotension. The results were confirmed by real-time PCR. Six functionally known genes (Igfbp1, Xdh, Sult1a1, Mawbp, Por, and Gstm1) and two expressed sequence tages (BI277460 and AI411345) were significantly upregulated. Four of these genes (Igfbp1, Xdh, Por, and Gstm1) have well-characterized functions in the cardiovascular system. The proteins corresponding to Xdh, Por, and Gstm1 are involved in the metabolism of reactive oxygen species (ROS). Because ROS can mediate endothelial dysfunction, we measured the aortic dilatory capacity in thoracic aortic rings. Indeed, vasodilator potency to acetylcholine was largely diminished in hypotensive animals, whereas sodium nitroprusside induced equivalent vasodilations in normotensive and hypotensive animals. The vasodilator potency of the endothelium was partially restored by the superoxide scavenger tiron. Hence, acute hypotension induces a diminished vasodilator potency of the endothelium due to an accelerated degradation of nitric oxide by ROS. The present physiogenomic approach is capable of detecting vasoregulatory mechanisms and may provide deeper insight into the genetics and physiology of blood pressure regulation.geneticsendotheliummicroarrayreactive oxygen species VASCULAR TONE is regulated by a dynamic balance of local chemical, neural, and humoral mechanisms. The systemic regulatory mechanisms synergize with local mechanisms and adjust specific vascular responses in different vascular beds. Because of its central role in volume and vascular resistance regulation (e.g., the renin-angiotensin-aldosterone system), the kidney constitutes a major component in the systemic control of blood pressure (35). Local control of blood pressure is largely affected by chemical conditions (pH, O 2 tension, and CO 2 tension) and the paracrine properties of the endothelium. The vascular endothelium releases several vasodilator and vasoconstrictor substances including prostaglandins, thromboxanes, nitric oxide (NO), endothelins, complex nucleotides, and reactive oxygen species (ROS) (17,29,40). At present, there is increasing evidence that vascular cytochrome P-450 metabolites of arachidonic acid (20-hydroxyeicosatetraenoic acid and epoxyeicosatrienoic acid) play an important role in the control of vascular tone and in the long-term cont...

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