T he CNS plays an integral role in blood pressure regulation, primarily through sympathetic activation and mediation of various neurohumoral factors such as angiotensin II (Ang II) and vasopressin. [1][2][3][4] Hormones such as these can access the circumventricular organs, which are adjacent to the cerebral ventricles and have a poorly formed blood brain barrier. The circumventricular organs implicated in blood pressure control include the organum vasculosum of the lamina terminalis (OVLT), the area postrema, the subfornical organ, and the anteroventral third ventricle (AV3V) region. 5 The AV3V region includes the median preoptic nucleus, the OVLT, and the periventricular nucleus and has been shown to play an important role in several behavioral, neural and hormonal functions involved in body fluid and cardiovascular homeostasis. 6,7 Electrolytic lesions that disrupt the AV3V region have been shown to abolish virtually all of the central actions of Ang II, including drinking behavior, sympathetic outflow, and vasopressin release. 6 Electrolytic lesions of this brain region abolish the centrally mediated pressor response to central and peripheral infusions of Ang II, as well as preventing and/or reversing several other forms of experimental hypertension. 5,6 In addition to central mechanisms, substantial evidence suggests that inflammation can contribute to the pathophysiology of hypertension. For example, inflammatory cells accumulate in the kidney and vasculature of hypertensive animals, and the prevention of this can lower blood pressure. 8 Recently, our laboratory has found that mice lacking T-lymphocytes are resistant to the development of both Ang II and DOCA-salt induced hypertension. 9 Adoptive transfer of T, but not B cells restored hypertension in these animals. Despite the growing evidence for the role of T cells in hypertension, the mechanisms underlying T-cell activation and vascular infiltration by T cells remain unclear. Given the importance of the CNS in regulating blood pressure, we hypothesized that the CNS could Original

Abstract-The circumventricular organs (CVOs) lack a well-formed blood-brain barrier and produce superoxide in response to angiotensin II and other hypertensive stimuli. This increase in central superoxide has been implicated in the regulation of blood pressure. The extracellular superoxide dismutase (SOD3) is highly expressed in cells associated with CVOs and particularly with tanycytes lining this region. To understand the role of SOD3 in the CVOs in blood pressure regulation, we performed intracerebroventricular injection an adenovirus encoding Cre-recombinase (5ϫ10 8 particles per milliliter) in mice with loxP sites flanking the SOD3 coding region (SOD3 loxp/loxp mice). An adenovirus encoding red-fluorescent protein was injected as a control. Deletion of CVO SOD3 increased baseline blood pressure modestly and markedly augmented the hypertensive response to low-dose angiotensin II (140 ng/kg per day), whereas intracerebroventricular injection of adenovirus encoding red-fluorescent protein had minimal effects on these parameters. Adenovirus encoding Cre-recombinase-treated mice exhibited increased sympathetic modulation of heart rate and blood pressure variability, increased vascular superoxide production, and T-cell activation as characterized by increased circulating CD69 ϩ /CD3 ϩ cells. Deletion of CVO SOD3 also markedly increased vascular T-cell and leukocyte infiltration caused by angiotensin II. We conclude that SOD3 in the CVO plays a critical role in the regulation of blood pressure, and its loss promotes T-cell activation and vascular inflammation, in part by modulating sympathetic outflow. These findings provide insight into how central signals produce vascular inflammation in response to hypertensive stimuli, such as angiotensin II. ⅐Ϫ by administration of membrane-targeted forms of SOD, SOD mimetics (eg, Tempol), or deletion of the gene encoding for the NADPH oxidase subunit p47phox reduces blood pressure in several experimental models of hypertension. [2][3][4] In addition, embryonic deletion of SOD3, which would be expected to increase extracellular O 2 ⅐Ϫ , augments hypertension in response to angiotensin (Ang) II or deoxycorticosterone acetate-salt challenge. 5,6 Although these studies support a role for SOD3 and oxidative stress in the genesis of hypertension, they do not address potential sites or mechanisms by which deletion of SOD3 augments hypertension. Potential sites where this enzyme could modulate blood pressure include the vasculature, the kidney, and the brain. In addition to oxidative stress, recent studies from our laboratory and others have also suggested an important role for peripheral T-lymphocyte activation and vascular inflammation in the development of Ang II-induced hypertension. The relationship between oxidative events in sites such as the central nervous system, T-cell activation, and vascular inflammation remain poorly understood.The purpose of the present studies was to explore the hypothesis that defects in brain SOD3 might participate in the development of hypertensio...

The present experiments examined whether in rats consuming diets with either high NaCl content (8%) or low Na+ content (0.01%) for 2 wk excitatory inputs to the rostral ventrolateral medulla (RVLM) would be altered. In chloralose-anesthetized rats, injection of glutamate into the RVLM elicited a pressor response that, compared with rats fed a control diet, was 50% larger in rats fed a diet containing 8% NaCl and was 25% smaller in rats fed a diet containing 0.01% Na+. Pressor responses produced by electrical stimulation of sciatic nerve afferents, as well as by microinjections into the RVLM ofl-dihydroxyphenylalanine or carbachol, were all potentiated by high dietary salt intake and reduced by low dietary salt intake. Dietary salt intake had no effect on pressor responses produced by intravenous injection of phenylephrine, indicating that salt-related alterations in cardiovascular responses produced by central activation could not be accounted for by changes in peripheral vascular reactivity. The decrease in arterial pressure produced by injection of glutamate into the nucleus of the solitary tract was also potentiated by the high salt diet, suggesting that the sensitivity of central baroreceptor reflex pathways may be altered by dietary NaCl. These results indicate that the amount of NaCl consumed in the diet can change the sensitivity of RVLM sympathoexcitatory neurons, and this change in sensitivity is not restricted to any particular class of cell surface receptors.

Inactivation of the tumor suppressor adenomatous polyposis coli, with the resultant activation of B-catenin, is the initiating event in the development of a majority of colorectal cancers. Krüppel-like factor 5 (KLF5), a proproliferative transcription factor, is highly expressed in the proliferating intestinal crypt epithelial cells. offsets the tumor-initiating activity of the Apc Min mutation by reducing the nuclear localization and activity of B-catenin.

Excess dietary sodium is a major contributing factor to the incidence and severity of hypertension. However, the precise mechanism or mechanisms by which salt contributes to the severity of hypertension are unknown. The region of the rostral ventrolateral medulla (RVLM) is a principal brain stem locus critical for the regulation of arterial blood pressure by the sympathetic nervous system. The purpose of this study was to determine if excess dietary sodium chloride might alter the function or responsiveness of neurons In the RVLM. Male Sprague-Dawiey rats were given either tap water or 0.9% sodium chloride solution to drink for 10 to 14 days. Excess sodium chloride did not affect baseline blood pressure. However, when neurons of the RVLM were stimulated by microinjections of L-glutamate, evoked increases in arterial pressure were potentiated in rats given sodium chloride. Augmented pressor responses could not be accounted for by increased vascular reactivity because both groups responded similarly to intravenously administered phenylephrine and norepinephrine. Additionally, electrical stimulation of descending spinal sympathoexcitatory axons produced identical pressor responses in both groups, indicating that altered synaptic transmission at central or peripheral neuroeffector junctions distal to the RVLM could not explain enhanced pressor responses produced by direct stimulation of RVLM cell somata. Finally, impaired arterial baroreceptor reflexes could not account for augmented RVLM pressor responses, as depressor and bradycardic responses produced by electrical stimulation of aortic baroreceptor afferents were not reduced in rats given excess dietary sodium chloride. These results indicate that increased dietary salt intake sensitizes RVLM sympathoexcitatory neurons and may predispose toward the exaggerated expression of hypertension, suggesting a potential link between salt, hypertension, and the brain. (NaCl) to the pathogenesis of hypertension has been debated for almost half a century. 12 Although an increase in NaCl intake is not invariably associated with elevated arterial blood pressure, a large subset of individuals exhibits fluctuations in arterial pressure when daily salt intake is varied. 35 However, a diet high in salt alone is not sufficient to produce hypertension in otherwise normotensive individuals but instead plays a permissive role in enabling the exaggerated expression of hypertension.3 Salt sensitivity of blood pressure has been studied intensively, but the mechanism or mechanisms by which increased dietary salt imparts enhanced sensitivity to hypertensive stimuli are not known.In several experimental models of hypertension, excess NaCl intake is essential for either the development or full expression of hypertension.611 Additionally, the central nervous system (CNS) and peripheral sympathetic nervous system contribute significantly to the maintenance of elevated arterial pressure in many of