The present investigation demonstrates that NO, but not prostacyclin, is essential for flow-mediated dilatation of large human arteries. Hence, this response can be used as a test for the L-arginine/NO pathway in clinical studies.
Background-The lymphatic system regulates interstitial tissue fluid balance, and lymphatic malfunction causes edema.The heart has an extensive lymphatic network displaying a dynamic range of lymph flow in physiology. Myocardial edema occurs in many cardiovascular diseases, eg, myocardial infarction (MI) and chronic heart failure, suggesting that cardiac lymphatic transport may be insufficient in pathology. Here, we investigate in rats the impact of MI and subsequent chronic heart failure on the cardiac lymphatic network. Further, we evaluate for the first time the functional effects of selective therapeutic stimulation of cardiac lymphangiogenesis post-MI. Methods and Results-We investigated cardiac lymphatic structure and function in rats with MI induced by either temporary occlusion (n=160) or permanent ligation (n=100) of the left coronary artery. Although MI induced robust, intramyocardial capillary lymphangiogenesis, adverse remodeling of epicardial precollector and collector lymphatics occurred, leading to reduced cardiac lymphatic transport capacity. Consequently, myocardial edema persisted for several months post-MI, extending from the infarct to noninfarcted myocardium. Intramyocardial-targeted delivery of the vascular endothelial growth factor receptor 3-selective designer protein VEGF-C C152S , using albumin-alginate microparticles, accelerated cardiac lymphangiogenesis in a dose-dependent manner and limited precollector remodeling post-MI. As a result, myocardial fluid balance was improved, and cardiac inflammation, fibrosis, and dysfunction were attenuated. Conclusions-We show that, despite the endogenous cardiac lymphangiogenic response post-MI, the remodeling and dysfunction of collecting ducts contribute to the development of chronic myocardial edema and inflammationaggravating cardiac fibrosis and dysfunction. Moreover, our data reveal that therapeutic lymphangiogenesis may be a promising new approach for the treatment of cardiovascular diseases. deleterious effects, including induction of blood vascular rarefaction and dysfunction and stimulation of cardiac fibrosis, contributing to the development of chronic heart failure . 14 Furthermore, many inflammatory mediators, and oxygen radicals generated during inflammation, as well, negatively affect lymphatic function, causing impairment of lymph flow and initiation of lymph edema and chronic inflammation. 15,16 It is noteworthy that clinically detectable myocardial edema, extending beyond the infarct zone, may persist for up to 6 to 12 months post-myocardial infarction (MI) in humans, which is suggestive of lymphatic insufficiency. 17,18Whether cardiac lymphatic dysfunction occurs after myocardial injury, and the impact this may have on myocardial fluid balance and cardiac inflammation, remains to be investigated. Moreover, although the advent of molecular lymphatic markers has fueled investigations into lymphatic anatomy, function, and growth in many organs, 19-21 only a handful of articles have assessed lymphangiogenesis in the heart. It was rec...
We have shown previously that preconditioning myocardium with four 5-minute episodes of ischemia and reperfusion dramatically limited the size of infarcts caused by a subsequent 40-minute episode of sustained ischemia. The current study was undertaken to assess whether the same preconditioning protocol slowed the loss of high energy phosphates, limited catabolite accumulation, and/or delayed ultrastructural damage during a sustained ischemic episode. Myocardial metabolites and ultrastructure in the severely ischemic subendocardial regions were compared between control and preconditioned canine hearts. Hearts (four to 10 per group) were excised after 0, 5, 10, 20, or In an attempt to separate the effects of catabolite accumulation from those of ATP depletion, we have examined the effects of repeated coronary occlusions. We hypothesized that repeated coronary occlusions might cause partial depletion of ATP, whereas intermittent reperfusion would wash out ischemic catabolites. In a recent study,' we proposed that multiple brief ischemic episodes actually might protect the heart from a subsequent sustained ischemic insult. To test this hypothesis, dogs were "preconditioned" with four 5-minute episodes of ischemia, each separated by 5 minutes of reperfusion, and then subjected immediately to a sustained occlusion of either 40 minutes or 3 hours. Control animals received either a single 40-minute or 3-hour occlusion. In the 40-minute study, infarcts in preconditioned hearts were smaller than controls at any level of collateral flow, averaging 25% of control infarct size. In the 3-hour study, preconditioning had no effect on infarct size.by guest on May 12, 2018
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