scholarly journals Functional Corpora Lutea Are Formed in Matrix Metalloproteinase Inhibitor-Treated Plasminogen-Deficient Mice

Endocrinology ◽  
2007 ◽  
Vol 148 (3) ◽  
pp. 1226-1234 ◽  
Author(s):  
Patrik Wahlberg ◽  
Ida Bodén ◽  
Josefin Paulsson ◽  
Leif R. Lund ◽  
Kui Liu ◽  
...  
Keyword(s):  
Matrix Metalloproteinase ◽  
Plasminogen Activator ◽  
Tissue Remodeling ◽  
Corpora Lutea ◽  
Wild Type ◽  
Serum Progesterone ◽  
Paracrine Factors ◽  
Proteolytic Activation ◽  
Luteal Function ◽  
Deficient Mice

Corpus luteum (CL) formation involves dramatic tissue remodeling and angiogenesis. To determine the functional roles of the plasminogen activator and matrix metalloproteinase (MMP) systems in these processes, we have studied CL formation and function in plasminogen (plg)-deficient mice, with or without treatment with the broad-spectrum synthetic MMP inhibitor galardin. Both the adult pseudopregnant CL model and the gonadotropin-primed immature mouse model were used. We found that CL formed normally not only in plasminogen-deficient mice and in galardin-treated wild-type mice, but also in galardin-treated plg-deficient mice, suggesting that neither of the plasminogen activator and MMP systems is essential for CL formation. Nevertheless, in plg-deficient mice, serum progesterone levels were reduced by approximately 50%, and the progesterone levels were not reduced further by galardin treatment. When CL from plg-deficient mice were stained for several molecular markers for CL development and regression, they appeared healthy and vascularized, and were indistinguishable from CL from wild-type mice. This implies that the reduced progesterone levels were not caused by impaired CL formation. Taken together, our data suggest that neither plasmin nor MMPs, alone or in combination, are required for CL formation. Therefore, the tissue remodeling and angiogenesis processes during CL formation may be mediated by redundant protease systems. However, the reduced serum progesterone levels in plg-deficient mice suggest that plasmin, but not MMPs, plays a role in maintenance of luteal function. This role may be performed through proteolytic activation of growth factors and other paracrine factors.

Urokinase-dependent plasminogen activation is required for efficient skeletal muscle regeneration in vivo

Blood ◽  
2001 ◽  
Vol 97 (6) ◽  
pp. 1703-1711 ◽  
Author(s):  
Frederic Lluı́s ◽  
Josep Roma ◽  
Mònica Suelves ◽  
Maribel Parra ◽  
Gloria Aniorte ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Plasminogen Activator ◽  
Muscle Regeneration ◽  
Plasminogen Activators ◽  
Skeletal Muscle Regeneration ◽  
Plasminogen Activation ◽  
Wild Type ◽  
Type Plasminogen Activator ◽  
Deficient Mice

Plasminogen activators urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA) are extracellular proteases involved in various tissue remodeling processes. A requirement for uPA activity in skeletal myogenesis was recently demonstrated in vitro. The role of plasminogen activators in skeletal muscle regeneration in vivo in wild-type, uPA-deficient, and tPA-deficient mice is investigated here. Wild-type and tPA−/− mice completely repaired experimentally damaged skeletal muscle. In contrast, uPA−/− mice had a severe regeneration defect, with decreased recruitment of blood-derived monocytes to the site of injury and with persistent myotube degeneration. In addition, uPA-deficient mice accumulated fibrin in the degenerating muscle fibers; however, the defibrinogenation of uPA-deficient mice resulted in a correction of the muscle regeneration defect. A similar severe regeneration deficit with persistent fibrin deposition was also reproducible in plasminogen-deficient mice after injury, suggesting that fibrinolysis by uPA-mediated plasminogen activation plays a fundamental role in skeletal muscle regeneration. In conclusion, the uPA-plasmin system is identified as a critical component of the mammalian skeletal muscle regeneration process, possibly because it prevents intramuscular fibrin accumulation and contributes to the adequate inflammatory response after injury. These studies demonstrate the requirement of an extracellular proteolytic cascade during muscle regeneration in vivo.

Myeloperoxidase deficiency ameliorates progression of chronic kidney disease in mice

2014 ◽  
Vol 307 (4) ◽  
pp. F407-F417 ◽  
Author(s):  
Alexander Lehners ◽  
Sascha Lange ◽  
Gianina Niemann ◽  
Alva Rosendahl ◽  
Catherine Meyer-Schwesinger ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Matrix Metalloproteinase ◽  
Collagen Type ◽  
Matrix Metalloproteinase 2 ◽  
Marker Genes ◽  
Wild Type ◽  
Renal Ablation ◽  
The Impact ◽  
Deficient Mice

Myeloperoxidase (MPO) is an enzyme expressed in neutrophils and monocytes/macrophages. Beside its well-defined role in innate immune defence, it may also be responsible for tissue damage. To identify the role of MPO in the progression of chronic kidney disease (CKD), we investigated CKD in a model of renal ablation in MPO knockout and wild-type mice. CKD was induced by 5/6 nephrectomy. Mice were followed for 10 wk to evaluate the impact of MPO deficiency on renal morbidity. Renal ablation induced CKD in wild-type mice with increased plasma levels of MPO compared with controls. No difference was found between MPO-deficient and wild-type mice regarding albuminuria 1 wk after renal ablation, indicating similar acute responses to renal ablation. Over the next 10 wk, however, MPO-deficient mice developed significantly less albuminuria and glomerular injury than wild-type mice. This was accompanied by a significantly lower renal mRNA expression of the fibrosis marker genes plasminogen activator inhibitor-I, collagen type III, and collagen type IV as well as matrix metalloproteinase-2 and matrix metalloproteinase-9. MPO-deficient mice also developed less renal inflammation after renal ablation, as indicated by a lower infiltration of CD3-positive T cells and F4/80-positive monocytes/macrophages compared with wild-type mice. In vitro chemotaxis of monocyte/macrophages isolated from MPO-deficient mice was impaired compared with wild-type mice. No significant differences were observed for mortality and blood pressure after renal ablation. In conclusion, these results demonstrate that MPO deficiency ameliorates renal injury in the renal ablation model of CKD in mice.

Low-Dose Irradiation Promotes Tissue Revascularization through Matrix Metalloproteinase-9 Mediated VEGF Release from Mast Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 648-648
Author(s):  
Koichi Hattori ◽  
Yuichi Ohki ◽  
Yayoi Sato ◽  
Shahin Rafii ◽  
Zena Werb ◽  
...  
Keyword(s):  
Mast Cells ◽  
Matrix Metalloproteinase ◽  
Tissue Regeneration ◽  
Low Dose ◽  
Wild Type ◽  
Vascular Regeneration ◽  
Dose Irradiation ◽  
Ischemic Tissue ◽  
Metalloproteinase 9 ◽  
Deficient Mice

Abstract Irradiation is one of the pillars in the treatment of malignancies. The combination of radiotherapy and anti-angiogenic strategies has been shown to increase the tumor response in various tumor models. The more than additive effect of irradiation and anti-angiogenic treatment suggested that irradiation might have a pro-angiogenic effect. However, the mechanism remained unclear. Bone marrow(BM)-derived progenitor cells contribute to tissue regeneration by promoting angiogenesis/vasculogenesis. We demonstrated that chemokine/cytokine mediated progenitor mobilization is dependent on the activation of matrix metalloproteinase-9 (MMP-9). Here, we show that following irradiation hematopoietic and endothelial progenitors are released into circulation in MMP-9 wild-type, but not MMP-9 deficient (−/−) mice. We have observed that low-dose irradiation fosters vascular regeneration in a limb ischemia model. Vascular regeneration was driven by the upregulation of MMP-9 mediating the release of soluble Kit-ligand (KitL) and increasing plasma vascular endothelial growth factor (VEGF), followed by mobilization of BM-derived hematopoietic and endothelial progenitor cells. Release of sKitL and production of VEGF were impaired in MMP-9-/- mice resulting in failure of mobilization of hematopoietic and endothelial progenitors, and delayed vessel formation in the ischemic limb. The blood vessels forming in the ischemic tissue of MMP-9−/− mice lacked smooth muscle cell coverage, whereas stable vessels were formed in MMP-9 wild-type animals. But which cell type might be responsible for the observed VEGF increase following irradiation? Mast cells are known to harbor a variety of growth factors and angiogenic factors, including VEGF and have been shown to have pro-angiogenic effects. We analyzed various tissues of irradiated and non-irradiated controls. The number of mast cells was increased in the irradiated muscle tissue in MMP-9 wild-type, but not MMP-9−/− mice. VEGF was mainly produced by mast cells in a MMP-9 dependent manner as determined by in situ hybridization. Likewise, the number of mast cells was increased in the ischemic tissue of MMP-9 wild-type, but not in MMP-9 deficient mice. We could show that both VEGF and KitL can promote mast cell migration and that irradiation-induced soluble KitL in collaboration with VEGF promoted migration of mast cells in vitro. Taken together, low-dose irradiation promoted hematopoietic and endothelial progenitor cell mobilization and activation of mast cells thereby promoting vasculogenesis/angiogenesis in a hind limb model. These data not only show a novel mechanism of neovascularization and tissue regeneration but suggest that low-dose irradiation can be used for therapeutic angiogenesis augmenting collateral vessel growth in ischemic tissues.

scholarly journals Plasminogen Activator Inhibitor-Type I Gene Deficient Mice Show Reduced Influx of Neutrophils in Ventilator-Induced Lung Injury

2011 ◽  
Vol 2011 ◽  
pp. 1-11
Author(s):  
Esther K. Wolthuis ◽  
Alexander P. J. Vlaar ◽  
Jorrit-Jan H. Hofstra ◽  
Joris J. T. H. Roelofs ◽  
Vivian de Waard ◽  
...  
Keyword(s):  
Lung Injury ◽  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Lavage Fluid ◽  
Type I ◽  
Wild Type ◽  
Ventilator Induced Lung Injury ◽  
Deficient Mice ◽  
Activator Inhibitor ◽  
Pai 1

Ventilator-induced lung injury (VILI) is associated with inhibition of the fibrinolytic system secondary to increased production of plasminogen activator inhibitor- (PAI-)1. To determine the role of PAI-1 on pulmonary coagulopathy and inflammation during mechanical ventilation, PAI-1 gene-deficient mice and their wild-type littermates were anesthetized (control), or anesthetized, tracheotomized and subsequently ventilated for 5 hours with either low tidal volumes () or high tidal volumes (). VILI was assessed by pulmonary coagulopathy, lung wet-to-dry ratios, total protein level in bronchoalveolar lavage fluid, neutrophil influx, histopathology, and pulmonary and plasma cytokine levels. Ventilation resulted in pulmonary coagulopathy and inflammation, with more injury following ventilation with as compared to . In PAI-1 gene-deficient mice, the influx of neutrophils in the pulmonary compartment was attenuated, while increased levels of pulmonary cytokines were found. Other endpoints of VILI were not different between PAI-1 gene-deficient and wild-type mice. These data indicate that a defect fibrinolytic response attenuates recruitment of neutrophils in VILI.

scholarly journals Impaired Vascular Remodeling after Endothelial Progenitor Cell Transplantation in MMP9-Deficient Mice Suffering Cortical Cerebral Ischemia

2015 ◽  
Vol 35 (10) ◽  
pp. 1547-1551 ◽  
Author(s):  
Anna Morancho ◽  
Feifei Ma ◽  
Verónica Barceló ◽  
Dolors Giralt ◽  
Joan Montaner ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Matrix Metalloproteinase ◽  
Vascular Remodeling ◽  
Progenitor Cell ◽  
Stroke Recovery ◽  
Wild Type ◽  
Endothelial Progenitor ◽  
Advanced Therapies ◽  
Metalloproteinase 9 ◽  
Deficient Mice

Endothelial progenitor cells (EPCs) are being investigated for advanced therapies, and matrix metalloproteinase 9 (MMP9) has an important role in stroke recovery. Our aim was to determine whether tissue MMP9 influences the EPC-induced angiogenesis after ischemia. Wild-type (WT) and MMP9-deficient mice (MMP9/KO) were subjected to cerebral ischemia and treated with vehicle or outgrowth EPCs. After 3 weeks, we observed an increase in the peri-infarct vessel density in WT animals but not in MMP9/KO mice; no differences were found in the vehicle-treated groups. Our data suggest that tissue MMP9 has a crucial role in EPC-induced vascular remodeling after stroke.

Essential role of endogenous tissue plasminogen activator through matrix metalloproteinase 9 induction and expression on heparin-produced cerebral hemorrhage after cerebral ischemia in mice

Blood ◽  
2004 ◽  
Vol 103 (7) ◽  
pp. 2610-2616 ◽  
Author(s):  
Bing-Qiao Zhao ◽  
Yasuhiko Ikeda ◽  
Hayato Ihara ◽  
Tetsumei Urano ◽  
WenYing Fan ◽  
...  
Keyword(s):  
Matrix Metalloproteinase ◽  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Cerebral Hemorrhage ◽  
Essential Role ◽  
Border Zone ◽  
Microglial Cells ◽  
Proteolytic Activation ◽  
Heparin Administration ◽  
Tissue Plasminogen

Abstract Cerebral hemorrhage associated with antithrombotic and thrombolytic therapy in acute stroke continues to present a major clinical problem. Rupture of the cerebral microvasculature involves the degradation and remodeling of extracellular matrix. Here we demonstrated that the delayed administration of heparin 3 hours after photothrombotic middle cerebral artery occlusion (MCAO) caused cerebral hemorrhage in wild-type (WT) mice but not in tissue plasminogen activator (tPA)–deficient knockout (KO) mice. Heparin administration increased tPA activity and its mRNA expression at 6 and 12 hours after MCAO in the ischemic hemispheres of WT mice. The expression of tPA was enhanced in microglial cells in the ischemic border zone. We also observed an exacerbation of matrix metalloproteinase (MMP) 9 expression at the mRNA level and its conversion to an active form after heparin administration in the ischemic hemisphere in WT mice but not in tPA KO mice. The increased MMP 9 expression was localized in microglial cells and endothelial cells. These findings suggest that endogenous tPA, through the enhancement of MMP 9 expression and proteolytic activation, plays an essential role in the pathogenesis of heparin-produced cerebral hemorrhage. Targeting tPA, MMP 9, or both may provide a new approach for preventing cerebral hemorrhage associated with antithrombotic therapy for stroke in humans.

Tissue plasminogen activator (tPA) increase neuronal damage after focal cerebral ischemia in wild-type and tPA-deficient mice

1998 ◽  
Vol 4 (2) ◽  
pp. 228-231 ◽  
Author(s):  
Yanming F. Wang ◽  
Stella E. Tsirka ◽  
Sidney Strickland ◽  
Philip E. Stieg ◽  
Sulpicio G. Soriano ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Neuronal Damage ◽  
Focal Cerebral Ischemia ◽  
Wild Type ◽  
Tissue Plasminogen ◽  
Deficient Mice

scholarly journals Uncovering Novel Reproductive Defects in Neurokinin B Receptor Null Mice: Closing the Gap Between Mice and Men

Endocrinology ◽  
2012 ◽  
Vol 153 (3) ◽  
pp. 1498-1508 ◽  
Author(s):  
Jasmine J. Yang ◽  
Claudia S. Caligioni ◽  
Yee-Ming Chan ◽  
Stephanie B. Seminara
Keyword(s):  
Pubertal Development ◽  
Hypogonadotropic Hypogonadism ◽  
Corpora Lutea ◽  
Wild Type ◽  
Neurokinin B ◽  
Gnrh Release ◽  
Estrous Cyclicity ◽  
Closing The Gap ◽  
Deficient Mice ◽  
Robust Response

Patients bearing mutations in TAC3 and TACR3 (which encode neurokinin B and its receptor, respectively) have sexual infantilism and infertility due to GnRH deficiency. In contrast, Tacr3−/− mice have previously been reported to be fertile. Because of this apparent phenotypic discordance between mice and men bearing disabling mutations in Tacr3/TACR3, Tacr3 null mice were phenotyped with close attention to pubertal development, estrous cyclicity, and fertility. Tacr3−/− mice demonstrated normal timing of preputial separation and day of first estrus, markers of sexual maturation. However, at postnatal d 60, Tacr3−/− males had significantly smaller testes and lower FSH levels than their wild-type littermates. Tacr3−/− females had lower uterine weights and abnormal estrous cyclicity. Approximately half of Tacr3−/− females had no detectable corpora lutea on ovarian histology at postnatal d 60. Despite this apparent ovulatory defect, all Tacr3−/− females achieved fertility when mated. However, Tacr3−/− females were subfertile, having both reduced numbers of litters and pups per litter. The subfertility of these animals was not due to a primary ovarian defect, because they demonstrated a robust response to exogenous gonadotropins. Thus, although capable of fertility, Tacr3-deficient mice have central reproductive defects. The remarkable ability of acyclic female Tacr3 null mice to achieve fertility is reminiscent of the reversal of hypogonadotropic hypogonadism seen in a high proportion of human patients bearing mutations in TACR3. Tacr3 mice are a useful model to examine the mechanisms by which neurokinin B signaling modulates GnRH release.

Leukocyte urokinase plasminogen activator receptor and PSGL1 play a role in endogenous arterial fibrinolysis

2009 ◽  
Vol 102 (12) ◽  
pp. 1212-1218 ◽  
Author(s):  
Xufang Bai ◽  
Jeffrey Weitz ◽  
Peter Gross
Keyword(s):  
Plasminogen Activator ◽  
High Speed ◽  
Wild Type ◽  
Urokinase Plasminogen Activator Receptor ◽  
Activated Platelets ◽  
Upa Receptor ◽  
Type Plasminogen Activator ◽  
Urokinase Type Plasminogen Activator ◽  
Plasminogen Activator Receptor ◽  
Deficient Mice

SummaryFibrin is an integral component of arterial thrombi. Using a mouse model of arteriolar thrombosis, high-speed fluorescence microscopy reveals that, within minutes, the fibrin content of thrombi rapidly increases and then decreases.The decrease in fibrin coincides with leukocyte binding to the thrombi, a process mediated by the interaction of leukocyte P-selectin glycoprotein ligand-1 (PSGL-1) with P-selectin on the surface of activated platelets. Because leukocytes possess urokinase-type plasminogen activator (uPA) activity,we used mice deficient in uPA or the uPA receptor (uPAR) to explore the contribution of leukocyte associated uPA to the loss of fibrin from these thrombi. Fibrin loss in both uPA-deficient mice and uPAR-deficient mice was reduced compared with that in wild-type controls.Transfusion of leukocytes from wild-type mice into uPAR-deficient mice restored fibrin loss to levels similar to that in wild-type mice. In contrast, transfusion of leukocytes from mice deficient in uPAR or PSGL-1 did not enhance fibrin loss. Thus, fibrin loss from microarteriolar thrombi is mediated, at least in part, by leukocyte-associated uPA in a process that requires leukocyte uPAR and PSGL-1.

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