Pioglitazone Prevents Capillary Rarefaction in Streptozotocin-Diabetic Rats Independently of Glucose Control and Vascular Endothelial Growth Factor Expression

Background/Aims: Reduction of capillary network density occurs early in the development of metabolic syndrome and may be relevant for the precipitation of diabetes. Agonists of the peroxisome proliferator-activated receptor (PPAR)-gamma transcription factor are vasculoprotective, but their capacity for structural preservation of the microcirculation is unclear. Methods: Male Wistar rats were rendered diabetic by streptozotocin and treated with pioglitazone in chow for up to 12 weeks. Capillary density was determined in heart and skeletal muscle after platelet endothelial cell adhesion molecule-1 (PECAM-1) immunostaining. Hallmarks of apoptosis and angiogenesis were determined. Results: Capillary density deteriorated progressively in the presence of hyperglycemia (from 971/mm(2) to 475/mm(2) in quadriceps muscle during 13 weeks). Pioglitazone did not influence plasma glucose, left ventricular weight, or body weight but nearly doubled absolute and relative capillary densities compared to untreated controls (1.2 vs. 0.6 capillaries/myocyte in heart and 1.5 vs. 0.9 capillaries/myocyte in quadriceps muscle) after 13 weeks of diabetes. No antiapoptotic or angiogenic influence of pioglitazone was detected while a reduced expression of hypoxia-inducible factor-3 alpha and PPAR coactivator-1 alpha (PGC-1 alpha) mRNA as well as vascular endothelial growth factor (VEGF) protein possibly occurred as a consequence of improved vascularization. Conclusion: Pioglitazone preserves microvascular structure in diabetes independently of improvements in glycemic control and by a mechanism unrelated to VEGF-mediated angiogenesis. Copyright (C) 2012 S. Karger AG, Base

Functional implications of Reactive Oxygen Species (ROS) in human blood vessels

Reactive oxygen species (ROS) play a significant role in the pathogenesis of human vascular disorders associated with endothelial dysfunction, such as atherosclerosis, hypertension, coronary artery disease, and diabetic vascular disease. Moreover, recent data show that ROS are also relevant in venous diseases such as venous insufficiency or varicose vein disease (Guzik et al. 2011). In general, the functional role of ROS in human vasculature is consistent with the majority of findings in animal models and cell culture, with main differences being related to the complexity of the system. This complexity is related not only to the concomitant expression of numerous oxidases (including Nox5) in human vessels in vivo but primarily to complicated regulation by many coinciding factors. While this is the case for every translational approach, for studies of reactive oxygen species, the task becomes particularly difficult. Furthermore, vascular pathologies in humans are much more dynamic and progress through more complex stages than observed in animal models. In humans, the sources and functional importance of ROS appear to differ at various stages of atherosclerotic plaque development. However, a number of solid studies have been performed on relatively large populations of subjects, and there is clear evidence as to the functional role of ROS in human vasculature and their regulation, which will be briefly discussed here. Similar to animal models, ROS are generated by all layers of the vascular wall, the endothelium, vascular smooth muscle cells (VSMCs) in the media, fibroblasts, and incoming inflammatory cells in the adventitia (Berry et al. 2000). In these compartments, ROS may have divergent sources and roles, although its effects on endothelial function and vascular nitric oxide bioavailability appear to be particularly important in relation to human vascular disease