A bstract : The formation of new blood vessels (angiogenesis) is essential for embryonic development and contributes to the pathogenesis of numerous disorders. In contrast, insufficient angiogenesis may lead to tissue ischemia and failure. The recent discovery of novel angiogenic molecules has initiated efforts to improve tissue perfusion via therapeutic angiogenesis. However, rational design of such treatment strategies mandates a better understanding of the molecular mechanisms of angiogenesis. In this brief review, the role of a prime angiogenic candidate, namely vascular endothelial growth factor (VEGF) and its homologues, in physiological and pathological angiogenesis will be discussed with particular attention to myocardial ischemia and heart failure. In addition, a novel interaction between the junctional protein vascular endothelial‐cadherin (VE‐cadherin) and VEGF, essential for the endothelial survival function of VEGF, will be reviewed.
The blood coagulation and the fibrinolytic (or plasminogen/plasmin) systems determine the balance between the formation and dissolution of blood clots, but in addition contribute to the pathogenesis of various cardiovascular disorders such as thrombosis, atherosclerosis and restenosis. Furthermore, they participate in a variety of other (patho)biological processes such as embryonic development, reproduction, wound healing, cancer and brain function. Two recently developed technologies, gene targeting and gene transfer, that allow to manipulate the genetic balance of these proteinase systems in a controllable manner have allowed to more definitively elucidate the biological role of these systems. This review summarizes the insights that have been obtained from the gene targeting studies and discusses the use of adenovirus-mediated transfer of fibrinolytic genes to study and possibly to develop novel strategies for the treatment of restenosis and thrombosis.
Homozygous plasminogen-deficient (Plg-/-) mice had a significantly reduced thrombolytic capacity toward intravenously injected 125I-fibrin labeled plasma clots prepared from Plg-/- murine plasma (9% +/- 3% lysis after 8 hours; (mean +/- SEM, n = 6), as compared with 82% +/- 8% in wild-type mice; P < .0001). Bolus injection of 1 mg purified murine plasminogen in 10- to 17-week-old Plg-/- mice increased the plasminogen antigen and activity levels at 8 hours to normal levels (130 +/- 5 micrograms/mL). Plasminogen administration was associated with significant restoration of thrombolytic potential (64% +/- 7% spontaneous clot lysis; P < .0001 versus lysis without plasminogen injection). Bolus injection of 1 mg plasminogen in homozygous tissue- type plasminogen activator-deficient (t-PA-/-) mice doubled the plasminogen antigen and activity levels after 8 hours and increased 125I-fibrin clot lysis at 8 hours from 13% +/- 3% to 34% +/- 5% (P = .008). Fibrinogen, t-PA antigen and alpha 2-antiplasmin activity levels after 8 hours were not significantly different in the groups with or without plasminogen injection. Injection of plasminogen induced a variable increase (on average 7- to 10-fold) of PAI-1, but no correlation with the extent of spontaneous clot lysis was observed. Histopathologic examination at the end of the experiments revealed that fibrin deposition in the liver of Plg-/- mice was slightly reduced 8 hours after bolus plasminogen injection (P = .007) and markedly reduced after 24 hours (P < .0001). Plasminogen antigen levels in liver extracts were comparable with those found in wild-type mice at 8 hours (130 +/- 20 versus 110 +/- 15 ng/mg protein) and decreased to 25 +/- 3.2 ng/mg protein at 24 hours. Thus, restoration of normal plasminogen levels in Plg-/- mice normalized the thrombolytic potential toward experimentally induced pulmonary emboli, and resulted in removal of endogenous fibrin deposits within 24 hours.
<b>Copyright information:</b>Taken from "Urokinase, a constitutive component of the inflamed synovial fluid, induces arthritis"Arthritis Research & Therapy 2002;5(1):R9-R17.Published online 17 Oct 2002PMCID:PMC154426.Copyright © 2003 Jin et al., licensee BioMed Central Ltd. This is an Open Access article: Media for any non-commercial purpose, provided this notice is presented along with the articles original URL. Arthritic knee joint 4 days after the LMW-uPA injection (60 pmol/joint). Infiltration of mononuclear cells in the synovial tissue is apparent. Original magnification × 10. Knee joint injected with PBS revealed no signs of inflammation. Original magnification × 10. JC, joint cavity; C, cartilage; ST, synovial tissue; P, pannus. Arrows indicate inflammatory cell infiltration in the synovium and pannus formation.
We conclude that a pressure gradient reversal in early diastole is always observed below a heart rate of 110 beats.min-1 and that isoprenaline and atropine affect the pattern of transmitral pressure gradients in a different way.
