Elevated dietary salt intake has previously been demonstrated to have dramatic effects on microvascular structure and function. The purpose of this study was to determine whether a high-salt diet modulates physiological angiogenesis in skeletal muscle. Male Sprague-Dawley rats were placed on a control diet (0.4% NaCl by weight) or a high-salt diet (4.0% NaCl) before implantation of a chronic electrical stimulator. After seven consecutive days of unilateral hindlimb muscle stimulation, animals on control diets demonstrated a significant increase in microvessel density in the tibialis anterior muscle of the stimulated hindlimb relative to the contralateral control leg. High salt-fed rats demonstrated a complete inhibition of this angiogenic response, as well as a significant reduction in plasma ANG II levels compared with those of control animals. To investigate the role of ANG II suppression on the inhibitory effect of high-salt diets, a group of rats that were fed high salt were chronically infused with ANG II at a low dose. Maintenance of ANG II levels restored stimulated angiogenesis to control levels in animals fed a high-salt diet. Western blot analysis indicated that inhibition of angiogenesis in high salt-fed rats was not due to changes in VEGF or VEGF receptor type 1 protein expression in response to stimulation; however, the degree to which VEGF receptor 2 protein increased with stimulation was significantly lower in high salt-fed animals. This study demonstrates an inhibitory effect of high salt intake on stimulated angiogenesis and suggests a critical role for ANG II suppression in mediating this antiangiogenic effect.
Objective-High dietary salt has been demonstrated to inhibit angiogenesis in skeletal muscle. The purpose of this study was to determine whether high salt impairs steady state muscle performance following a chronic stimulation protocol.Methods-Sprague-Dawley rats were placed on a control diet (CD, 0.4% NaCl) or high salt diet (HSD, 4.0% NaCl) prior to implantation of an electrical muscle stimulator. In chronically stimulated animals, hind limb muscles were stimulated to contract eight hours daily for seven days. Sham animals received a stimulator that was never activated.Results-Following chronic stimulation, tibialis anterior (TA) muscles of animals on CD demonstrated an 84.6% increase in force of contraction at the end of an acute stimulation bout relative to sham animals fed CD. Decreased muscle fatigue was associated with an increase in capillaries per TA fiber (C:F). Chronic stimulation in HSD rats induced a smaller improvement (52.2%) in final force compared to HSD sham rats. This impairment of muscle performance in high salt-fed rats correlated with inhibited angiogenesis. Infusion of angiotensin II in HSD animals restored angiogenesis and muscle fatigue to CD levels.Conclusions-This study suggests that angiogenic inhibition by high salt is associated with impaired skeletal muscle performance following chronic stimulation.
Objective-The purpose of this study was to determine whether a high-salt diet modulates physiological angiogenesis in skeletal muscle by altering angiotensin II (ANGII) and vascular endothelial growth factor (VEGF) levels.Methods-Sprague-Dawley rats were placed on a control diet (0.4% NaCl by weight) or high-salt diet (4.0% NaCl) prior to treatment with the vasodilator prazosin in the drinking water. In addition, a group of animals fed high salt were infused intravenously with ANGII at a low dose to prevent ANGII suppression by high salt, and a group of rats fed control diet were treated with the angiotensin II type I (AT 1 ) receptor blocker losartan and prazosin.Results-Prazosin induced significant angiogenesis in the tibialis anterior muscle after 1 week of treatment. High-salt-fed rats demonstrated a complete inhibition of this angiogenic response. Maintenance of ANGII levels restored prazosin-induced angiogenesis in animals fed a high-salt diet. In addition, losartan treatment blocked prazosin-induced angiogenesis in animals on a control diet. Western blot analysis indicated that prazosin-induced angiogenesis was independent of changes in muscle levels of VEGF.Conclusions-This study demonstrates an inhibitory effect of high salt intake on prazosin-induced angiogenesis. Further, these results indicate that ANGII acting through the AT 1 receptor is a critical pathway in this model of angiogenesis.Keywords blood pressure; losartan; microcirculation Angiogenesis, the growth of new capillaries in the microvasculature, is an important adaptation made by tissues in a variety of physiological and pathological states. This complex process commonly involves endothelial cell proliferation, migration, and tube formation and is impacted by various humoral, mechanical, and metabolic stimuli. An increase in metabolic demand, such as that seen in skeletal muscle during exercise training and electrical stimulation of muscle contraction, has been demonstrated to induce angiogenesis [1,3,21], presumably as an adaptation that increases both the delivery of critical metabolic substrates and the removal Address correspondence to Andrew S. Greene, Department of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI. E-mail: agreene@mcw.edu. Publisher's Disclaimer: Full terms and conditions of use: http://www.informaworld.com/terms-and-conditions-of-access.pdf This article maybe used for research, teaching and private study purposes. Any substantial or systematic reproduction, re-distribution, re-selling, loan or sub-licensing, systematic supply or distribution in any form to anyone is expressly forbidden. The publisher does not give any warranty express or implied or make any representation that the contents will be complete or accurate or up to date. The accuracy of any instructions, formulae and drug doses should be independently verified with primary sources. The publisher shall not be liable for any loss, actions, claims, proceedings, demand or costs or damages whatsoever or howsoever caused...
Considerable progress has been made in the last decade in the engineering and construction of a number of artificial tissue types. These constructs are typically viewed from the perspective of possible sources for implant and transplant materials in the clinical arena. However, incorporation of engineered tissues, often referred to as three-dimensional (3D) cell culture, also offers the possibility for significant advancements in research for physiological genomics. These 3D systems more readily mimic the in vivo setting than traditional 2D cell culture, and offer distinct advantages over the in vivo setting for some organ systems. As an example, cardiac cells in 3D culture 1) are more accessible for siRNA studies, 2) can be engineered with specific cell types, and 3) offer the potential for high-throughput screening of gene function.Here the state-of-the-art is reviewed and the applications for engineered tissue in genomics research are proposed. The ability to use engineered tissue in combination with genomics creates a bridge between traditional cellular and in vivo studies that is critical to enabling the transition of genetic information into mechanistic understanding of disease processes.
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