Plasminogen activator inhibitor-1 (PAI-1), an endogenous inhibitor of a major fibrinolytic factor, tissue-type plasminogen activator, can both promote and inhibit angiogenesis. However, the physiologic role and the precise mechanisms underlying the angiogenic effects of PAI-1 remain unclear. In the present study, we report that pharmacologic inhibition of PAI-1 promoted angiogenesis and prevented tissue necrosis in a mouse model of hind-limb ischemia. Improved tissue regeneration was due to an expansion of circulating and tissue-resident granulocyte-1 marker (Gr-1 ؉ ) neutrophils and to increased release of the angiogenic factor VEGF-A, the hematopoietic growth factor kit ligand, and G-CSF. Immunohistochemical analysis indicated increased amounts of fibroblast growth factor-2 (FGF-2) in ischemic gastrocnemius muscle tissues of PAI-1 inhibitor-treated animals. Ab neutralization and genetic knockout studies indicated that both the improved tissue regeneration and the increase in circulating and ischemic tissue-resident Gr-1 ؉ neutrophils depended on the activation of tissuetype plasminogen activator and matrix metalloproteinase-9 and on VEGF-A and FGF-2. These results suggest that pharmacologic PAI-1 inhibition activates the proangiogenic FGF-2 and VEGF-A pathways, which orchestrates neutrophil-driven angiogenesis and induces cell-driven revascularization and is therefore a potential therapy for ischemic diseases. IntroductionApproximately 500 to 1000 people per million per year are diagnosed with critical ischemia of the limb, which in most cases results in serious morbidity and mortality. Therapeutic restoration of blood flow by, for example, the induction of the formation of new capillaries (angiogenesis) is the ultimate goal for critical limb ischemia patients. Growth of new blood vessels in the adult occurs through angiogenesis or arteriogenesis (vessel maturation via recruitment of smooth muscle cells) and vasculogenesis (mobilization of BM-derived cells). 1,2 In contrast to promising results from animal studies, administration of proangiogenic factors such as fibroblast growth factor 2 (FGF-2, also known as basic FGF) or VEGF-A failed to induce significant improvement in ischemia in several phase 1 clinical trials. 3 The plasminogen activation system and matrix metalloproteinases (MMPs), which can cleave growth factors, growth factor receptors, and adhesion molecules and mediate the extracellular matrix degradation that is necessary for cell migration, are widely recognized as being involved in the process of angiogenesis. 2,4 Although plasminogen activator inhibitor-1 (PAI-1) is one of the primary regulators of the fibrinolytic system, it also has dramatic effects on cell adhesion, detachment, and migration 5 and can inhibit cellular migration by affecting cell adhesion. 6,7 PAI-1-deficient (PAI-1 Ϫ/Ϫ ) mice showed improved vascular wound healing in models of perivascular electric or transluminal mechanical injury 8 due to improved migration of PAI-1 Ϫ/Ϫ smooth muscle cells. The 52-kDa serine protease inh...
HSC fate decisions are regulated by cellintrinsic and cell-extrinsic cues. The latter cues are derived from the BM niche. Membrane-type 1 matrix metalloproteinase (MT1-MMP), which is best known for its proteolytic role in pericellular matrix remodeling, is highly expressed in HSCs and stromal/niche cells. We found that, in MT1-MMP ؊/؊ mice, in addition to a stem cell defect, the transcription and release of kit ligand (KitL), stromal cell-derived factor-1 (SDF-1/CXCL12), erythropoietin (Epo), and IL-7 was impaired, resulting in a trilineage hematopoietic differentiation block, while addition of exogenous KitL and SDF-1 restored hematopoiesis. Further mechanistic studies revealed that MT1-MMP activates the hypoxia-inducible factor-1 (HIF-1) pathway via factor inhibiting HIF-1 (FIH- 1 IntroductionThe adult hematopoietic system is maintained by a small number of HSCs that reside in the BM in a specialized microenvironment (the niche). 1,2 Here, HSCs undertake fate decisions including differentiation to progenitor cells and self-renewal, which ensures a lifelong supply of terminally differentiated blood cells. Intrinsic cellular programming and external stimuli such as adhesive interactions with the microenvironmental stroma and cytokine activities regulate HSC fate. However, it is unclear how niche factor production is controlled to adjust to external demand with a fine-tuned response.Hypoxia-inducible factors (HIFs) consist of an ␣ (HIF-␣) and a  (HIF-, or ARNT) subunit and activate the expression of genes encoding proteins that regulate cell metabolism, motility, angiogenesis, hematopoiesis, and other functions. HSCs maintain cell-cycle quiescence by regulating HIF-1␣ levels. 3,4 Mice with mutations in the heterodimeric transcription factor HIF develop extensive hematopoietic pathologies: embryos lacking Arnt have defects in primitive hematopoiesis. 5 Mice lacking endothelial PAS domain protein 1 (EPAS1, also known as HIF-2alpha/HRF/HLF/MOP3), a second HIF family member, exhibited pancytopenia, and it was shown that EPAS1 is necessary to maintain a functional microenvironment in the BM for effective hematopoiesis. 6 HIFs bind to canonical DNA sequences in the promoters or enhancers of target genes such as erythropoietin (Epo), vascular endothelial growth factor-A, SDF-1␣/CXCL12, angiopoietin-2, platelet-derived growth factor-B and Kit Ligand (KitL)/stem cell factor, which are involved in HSC maintenance within the BM niche. 7-10 The chemokine SDF-1␣/CXCL12 (SDF-1␣) is expressed by perivascular, endosteal, mesenchymal stem and progenitor cells as well as by osteoblasts. 11,12 SDF-1␣ deficiency leads to a reduction in HSCs and impaired B-cell development in mice. 13,14 IL-7 is another stromal cell-derived niche factor, which, in cooperation with CXCL12, functions at sequential stages of B-cell development. 15,16 IL-7 or IL-7R deficiency results in impaired B-cell development. 17,18 Proteases such as matrix metalloproteinase-9 (MMP-9) and the serine proteinase plasmin(ogen) regulate HSC fate through KitL release i...
Ischemia of the heart, brain, and limbs is a leading cause of morbidity and mortality worldwide. Treatment with tissue type plasminogen activator (tPA) can dissolve blood clots and can ameliorate the clinical outcome in ischemic diseases. But the underlying mechanism by which tPA improves ischemic tissue regeneration is not well understood. Bone marrow (BM)-derived myeloid cells facilitate angiogenesis during tissue regeneration. Here, we report that a serpin-resistant form of tPA by activating the extracellular proteases IntroductionThe fibrinolytic system includes a broad spectrum of proteolytic enzymes with physiologic and pathophysiologic functions in several processes such as hemostatic balance, tissue remodeling, tumor invasion, reproduction, and angiogenesis.The serine protease plasmin is responsible for the degradation of fibrin into soluble degradation products (fibrinolysis). Plasmin is generated through cleavage of the proenzyme plasminogen (Plg) by the urokinase plasminogen activator (uPA) or tissue-type plasminogen activator (tPA). tPA consists of a kringle-and trypsin-like serine protease domain. 1 The activity of uPA and tPA is regulated by specific plasminogen activator inhibitors. In the absence of fibrin, tPA displays low activity toward Plg. 2 In the presence of fibrin this activity is 2 orders of magnitude higher. The catalytic efficiency of tPA for activation of cell-bound Plg is approximately 10-fold higher than that in solution. Most cells bind Plg through its lysine binding sites with a high capacity but a relatively low affinity. 3 Plg receptors such as the integrin ␣M2 play an important role in macrophage motility. 4 CD11b/CD18 cells adhere to fibrin, but tPA by its ability to bind to CD11b, has been shown to induce local fibrinolysis and to render adherent cells into migrating cells. 5 tPA has been shown to have numerous biologic functions. For example, within the central nervous system (reviewed by Melchor and Strickland 6 ) tPA is expressed by neurons and microglial cells (resident macrophages of the brain and spinal cord), where it can generate plasmin to degrade a variety of nonfibrin substrates (eg, -amyloid), can act as a direct protease without Plg involvement (eg, for the activation of latent platelet-derived growth factor-CC), or can function as a nonproteolytic modulator (eg, of the N-methyl-D-aspartate receptors).Besides their fibrinolytic activities, plasmin and Plg activators are also implicated in tissue proliferation and cellular adhesion, because they can proteolytically degrade the extracellular matrix (ECM) and regulate the activation of both growth factors and matrix metalloproteinases (MMPs; for review, see Zorio et al 7 ). PAs and plasmin generation in specific microenvironments in the bone marrow (BM) may be one of the factors orchestrating hematopoiesis. 8,9 Plg activation promotes the release of Kit ligand from BM stromal cells. 9,10 Plasmin can cleave thrombopoietin, the master cytokine of megakaryopoiesis and platelet production, thereby decreasing its biol...
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