Endothelial Dysfunction in Cardiovascular Diseases

Endothelium is the inner most cell layer of blood vessels. Endothelial cells make special barrier that separate blood from extravascular tissues. Intact endothelium regulates vascular tone and permeability and maintains non-inflammatory, anti-thrombotic surface. Through its ability to express pro-coagulants, anticoagulants, vasoconstrictors, vasodilators, cell adhesion molecules, and cytokines, the endothelium has emerged as one of the pivotal regulators of vascular homeostasis. Under physiological conditions, endothelial cell sustains a vasodilatory, anticoagulant, and fibrinolytic state in which coagulation, platelet adhesion, as well as leukocyte activation and inflammation are suppressed. In contrast, during endothelial disturbances, a prothrombotic and pro-inflammatory state of vasoconstriction gets support from the endothelial surface. Release of platelet-activating factor (PAF) and endothelin-1 promotes vasoconstriction, whereas production of von Willebrand factor (vWF), tissue factor (TF), and plasminogen activator inhibitor (PAI)-1 shifts the haemostatic balance towards a procoagulant state. Several factors like infection, hyperglycaemia, hyperlipidaemia, malignancy, oxidative stress, and aging can interfere in endothelial function. It is believed that most of the cardiovascular diseases originate from endothelial dysfunction. Endothelial dysfunction has been shown to be involved in atherosclerosis, thrombosis, hypertension, diabetes, and other cardiovascular diseases. In this review we will specifically highlight the role of endothelial dysfunction in development of cardiovascular diseases

Inhibition of snake venom induced sterile inflammation and PLA2 activity by Titanium dioxide Nanoparticles in experimental animals.

Sterile inflammation (SI) is an essential process in response to snakebite and injury. The venom induced pathophysiological response to sterile inflammation results into many harmful and deleterious effects that ultimately leads to death. The available treatment for snakebite is antiserum which does not provide enough protection against venom-induced pathophysiological changes like haemorrhage, necrosis, nephrotoxicity and often develop hypersensitive reactions. In order to overcome these hindrances, scientists around the globe are searching for an alternative therapy to provide better treatment to the snake envenomation patients. In the present study TiO2 (Titanium dioxide)-NPs (Nanoparticles) has been assessed for antisnake venom activity and its potential to be used as an antidote. In this study, the synthesis of TiO2-NPs arrays has been demonstrated on p-type Silicon Si  substrate (∼30 ohm-cm) and the surface topography has been detected by Field-emission scanning electron microscopy (FESEM). The TiO2-NPs successfully neutralized the Daboia russelii venom (DRV) and Naja kaouthia venom (NKV)-induced lethal activity. Viper venom induced haemorrhagic, coagulant and anticoagulant activities were effectively neutralized both in in-vitro and in vivo studies. The cobra and viper venoms-induced sterile inflammatory molecules (IL-6, HMGB1, HSP70, HSP90, S100B and vWF) were effectively neutralised by the TiO2-NPs in experimental animals

Decorin is a novel VEGFR-2-binding antagonist for the human extravillous trophoblast

Extravillous trophoblasts (EVT) of the human placenta invade the uterine decidua and its arteries to ensure successful placentation. We previously identified two decidua-derived molecules, TGF-β and a TGF-β-binding proteoglycan decorin (DCN), as negative regulators of EVT proliferation, migration, and invasiveness and reported that DCN acts via multiple tyrosine kinase receptors [epidermal growth factor-receptor (EGF-R), IGF receptor-1 (IGFR1), and vascular endothelial growth factor 2 receptor (VEGFR-2)]. Because binding of DCN toVEGFR-2 has never been reported earlier, present study explored this binding, the approximate location of VEGFR-2-binding site in DCN, and its functional role in our human first trimester EVT cell line HTR-8/SVneo. Based on far-Western blotting and coimmunoprecipitation studies, we report that DCN binds both native (EVT expressed) and recombinant VEGFR-2 and that this binding is abrogated with a VEGFR-2 blocking antibody, indicating an overlap between the ligand-binding and the DCN-binding domains of VEGFR-2. We determined that 125I-labeled VEGF-E (a VEGFR-2 specific ligand) binds EVT with a dissociation constant (K d) of 566 pM, and DCN displaced this binding with an inhibition constant (K i) of 3.93-5.78 nM, indicating a 7- to 10-fold lower affinity of DCN for VEGFR-2. DCN peptide fragments derived from the leucine rich repeat 5 domain that blocked DCN-VEGFR-2 interactions or VEGF-E binding in EVT cells also blocked VEGF-A- and VEGF-E-induced EVT cell proliferation and migration, indicative of functional VEGFR-2-binding sites of DCN. Finally, DCN inhibited VEGF-E-induced EVT migration by interfering with ERK1/2 activation. Our findings reveal a novel role of DCN as an antagonistic ligand for VEGFR-2, having implications for pathophysiology of preeclampsia, a trophoblast hypoinvasive disorder in pregnancy, and explain its antiangiogenic function. © 2011 by The Endocrine Society