Calcific aortic stenosis (CAS) is the most common valvular disease in Western countries. Histological findings in patients with CAS extremely resemble those of atherosclerosis and include accumulation and modification of lipoproteins, inflammation, extracellular matrix remodeling, and calcification. Angiogenesis is another prominent feature of CAS; however, there is only a limited amount of data available regarding the mechanisms behind the pathological neovascularization of a structure that is originally avascular. The present study aims to identify the molecular basis that regulates blood vessel growth in stenotic aortic valves, focusing on the role of HIF-1α and VEGF pathway. A total of 19 native degenerating aortic valves obtained at valve replacement surgery have been processed for Western blot, immunohistochemical, morphometric, and ultrastructural analyses. First, we have demonstrated the adverse ECM remodeling and the significant thickening of the leaflet also showing that HIF-1α and VEGF are significantly upregulated in the stenotic valves, are locally produced and colocalize with angiogenesis and areas of calcification. Next, we have characterized, for the first time to the best of our knowledge, the morphological features of the neovasculature evidencing the presence of intact blood vessels in close proximity to the mineralized zones. These results suggest that the complex structural remodeling of the matrix might reduce oxygen availability in the valve cusp contributing to the stabilization of HIF-1α that in turn induces a metabolic adaptation through the upregulation of VEGF and the formation of new blood vessels not only to overcome the hypoxic state but also to sustain the calcification process.
The main aim of this study was the investigation of the rheological properties of Red Blood Cells (RBCs) obtained from subjects admitted to blood donors, associated with the lipid profile of High-Density Lipoprotein Cholesterol (HDL-C), Low-Density Lipoprotein Cholesterol (LDL-C), Triglyceride (TG) and Total Cholesterol (TOT-C). The deformability index of RBCs was determined by using a Dynamic Stress Rheometer (DSR-500) under oxidative injury induced by 2.2'-azo-bis (2-amidinopropane) dihydrochloride (AAPH). An increased rigidity of RBCs in subjects with borderline level of hyperlipidemia was found, compared with the control group. In order to explain the reason for the reduced deformability, a borderline group was studied for the evaluation of anionic permeability on membrane, haemolysis and morphological changes induced by AAPH, as well as ThioBarbituric Acid Reactive Substances (TBARs) generation. Haemolysis by AAPH indicated a decrease of globular resistance in the borderline group, furthermore, the elevated values of TBARs suggested lipid peroxidative damage to the RBCs membrane associated with morphological changes and anion permeability alterations. Our study shows the correlation between biochemical and morphological parameters of RBCs and their rheological behavior during oxidative injury. Rheological studies might be useful as a clinical and diagnostic monitoring technique and provide support for further research.
Our data show that Ang II, via AT1 receptor, modulates calcium concentration involving T-type calcium channel and L-type calcium channel but only the calcium influx via T-type calcium channels regulates endothelial cell migration which is essential for angiogenesis.
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