1,326 publications from this institution
A bstract : Efforts to therapeutically stimulate or inhibit vessel growth have been primarily focused on vascular endothelial growth factor (VEGF) and its receptor VEGFR‐2 (Flk‐1), while little attention has been devoted to the therapeutic potential for angiogenic disorders of placental growth factor (PlGF), a VEGF family member, and its receptor VEGFR‐1 (Flt‐1). However, recent developments and insights could shift that focus to P1GF and Flt‐1. Indeed, PlGF stimulated angiogenesis and collateral growth in ischemic heart and limb with at least a comparable efficiency to VEGF and did not cause side effects associated with VEGF, such as edema or hypotension. An anti‐Flt‐1 antibody suppressed neovascularization in tumors and ischemic retina, and angiogenesis and inflammatory joint destruction in arthritis. The anti‐Flt‐1 antibody also reduced atherosclerotic plaque growth and vulnerability, but the atheroprotective effect was not due to reduced plaque neovascularization. The anti‐inflammatory effects of the anti‐Flt‐1 antibody were attributable to a reduced mobilization of bone marrow‐derived myeloid progenitors into the peripheral blood, a reduced mobilization/differentiation (and impaired infiltration) of Flt‐1‐expressing leukocytes into inflamed tissues, and a defective activation of myeloid cells. Thus, PlGF and Flt‐1 constitute potential candidates for therapeutic modulation of angiogenesis and inflammation.
Many studies suggest that the plasminogen activator (PA) system plays a role in the proteolytic degradation of the follicle wall at the time of ovulation. Consistently, the ovulation efficiency is reduced by 26% in mice where both physiological PA genes have been inactivated. To reveal the mechanism behind reduced ovulation efficiency in PA‐deficient mice and its effect on ovarian proteolysis, we have studied the regulation of plasmin activity in the ovaries of 25‐day‐old wild‐type mice and mice with deficient PA gene function during gonadotropin‐induced ovulation. In wild‐type mice the plasmin activity was low in ovarian extracts from mice treated with pregnant mare's serum gonadotropin. However, this activity was increased between 2–8 h after an ovulatory dose of human choriogonadotropins. In mice lacking either tissue‐type PA (tPA) or PA inhibitor type 1 (PAI‐1) the plasmin activity levels prior to ovulation were similar to wild‐type mice, while extracts prepared from urokinase‐type PA (uPA) deficient mice had 10% or less of the plasmin activity. This indicates that most of the plasmin activity in the mouse ovary is generated by uPA. In addition, as the ovulation efficiency is impaired in tPA/uPA‐deficient mice but appears normal in uPA‐deficient mice, our data indicates that the amount of plasmin generated by PAs prior to ovulation in wild‐type mice greatly exceeds the amount required for efficient ovulation.
Background: Inhibition of angiogenesis is currently hot topic in the search for an effective treatment for hepatocellular carcinoma (HCC). Up till recently, the focus was mainly on VEGF, an important regulator in the pathologic and physiologic angiogenesis. Although promising results are seen by inhibiting the VEGF-pathway, patients often suffer from major side effects. Placental growth factor (PlGF) is a VEGF analogue only involved in pathologic angiogenesis and its inhibition has the potential to restrain tumour growth, without affecting healthy organs. Therefore, we assessed whether administration of PlGF-antibodies could serve as a potential therapy for HCC in mice.\nMethods: 5-week-old male mice (sv129) received intraperitoneal (ip) injections once per week with N-nitrosodiethylamine (35 mg/kg bodyweight) or saline , which gives rise to HCC after 25W in WT. PlGF-knock-out mice (PlGF-/-) received weekly ip DEN-injections and were compared with their WT counterparts. At 26W, WT mice were treated with twice a week with murine monoclonal PlGF-antibodies (20 mg/kg anti-PlGF) or IgG for 5W and 10W. \nResults: By 25 weeks of DEN treatment, 29% of the WT mice but none of the PlGF-/- mice had succumbed to the disease (p = 0,056). Also, treatment of DEN-injected HCC mice from 25 weeks for 5 weeks with 5D11D4 (ThromboGenics N.V.) or IgG showed a significant difference in mortality. While 45% died in the control IgG group, only 23% mortality was observed in the anti-PlGF group (N=48; P < 0.05). Also, the liver/body weight ratio was 0.057 ± 0.003 in the control group versus 0.042 ± 0.004 in the 5D11D4 group (N=19; P < 0,05). After 10W treatment 90% died in the control IgG group, while only 41 % mortality was observed in the anti-PlGF group (N = 11, P < 0,05). No mortality was observed in mice injected with saline instead of DEN, followed by 5 wks of treatment with anti-PlGF or IgG. The liver/body weight ratio was 0.038 ± 0.001 in the saline and IgG group versus 0.041 ± 0.002 in the anti-PlGF group (N=12, P = 0,27).\nFigure 1: left: Mean survival of IgG and aPlGF treated mice ; right: mean survival of PlGF knock out mice and WT’s during DEN-induction \nConclusion: Our study showed that administration of 20 mg/kg anti-PlGF twice a week, has a positive effect on survival in mice with HCC. The liver/bodyweight ratio of anti-PlGF treated mice was significantly lower than in the control IgG group, showing a specific effect on liver tumours. Treatment of anti-PlGF in healthy mice did not induce negative side effects. Therefore, treatment with PlGF antibodies might serve as a promising systemic treatment in hepatocellular carcinoma patients.
