Involvement of placental growth factor in Wallerian degeneration

in Glia (2011), 59(3), 379-396

Wallerian degeneration (WD) is an inflammatory process of nerve degeneration, which occurs more rapidly in the peripheral nervous system compared with the central nervous system, resulting, respectively ... [more ▼]

Wallerian degeneration (WD) is an inflammatory process of nerve degeneration, which occurs more rapidly in the peripheral nervous system compared with the central nervous system, resulting, respectively in successful and aborted axon regeneration. In the peripheral nervous system, Schwann cells (SCs) and macrophages, under the control of a network of cytokines and chemokines, represent the main cell types involved in this process. Within this network, the role of placental growth factor (PlGF) remains totally unknown. However, properties like monocyte activation/attraction, ability to increase expression of pro-inflammatory molecules, as well as neuroprotective effects, make it a candidate likely implicated in this process. Also, nothing is described about the expression and localization of this molecule in the peripheral nervous system. To address these original questions, we decided to study PlGF expression under physiological and degenerative conditions and to explore its role in WD, using a model of sciatic nerve transection in wild-type and Pgf(-/-) mice. Our data show dynamic changes of PlGF expression, from periaxonal in normal nerve to SCs 24h postinjury, in parallel with a p65/NF-κB recruitment on Pgf promoter. After injury, SC proliferation is reduced by 30% in absence of PlGF. Macrophage invasion is significantly delayed in Pgf(-/-) mice compared with wild-type mice, which results in worse functional recovery. MCP-1 and proMMP-9 exhibit a 3-fold reduction of their relative expressions in Pgf(-/-) injured nerves, as demonstrated by cytokine array. In conclusion, this work originally describes PlGF as a novel member of the cytokine network of WD. [less ▲]

Further pharmacological and genetic evidence for the efficacy of PlGF inhibition in cancer and eye disease.

in Cell (2010), 141(1), 178-90

Our findings that PlGF is a cancer target and anti-PlGF is useful for anticancer treatment have been challenged by Bais et al. Here we take advantage of carcinogen-induced and transgenic tumor models as ... [more ▼]

Our findings that PlGF is a cancer target and anti-PlGF is useful for anticancer treatment have been challenged by Bais et al. Here we take advantage of carcinogen-induced and transgenic tumor models as well as ocular neovascularization to report further evidence in support of our original findings of PlGF as a promising target for anticancer therapies. We present evidence for the efficacy of additional anti-PlGF antibodies and their ability to phenocopy genetic deficiency or silencing of PlGF in cancer and ocular disease but also show that not all anti-PlGF antibodies are effective. We also provide additional evidence for the specificity of our anti-PlGF antibody and experiments to suggest that anti-PlGF treatment will not be effective for all tumors and why. Further, we show that PlGF blockage inhibits vessel abnormalization rather than density in certain tumors while enhancing VEGF-targeted inhibition in ocular disease. Our findings warrant further testing of anti-PlGF therapies. [less ▲]

Expression and role of Placental Growth Factor (PLGF) in the inflammatory context resulting from nerve injury, the Wallerian Degeneration.

Poster (2008, November)

Expression and role of Placental Growth Factor (PLGF) in the inflammatory context resulting from nerve injury, the Wallerian Degeneration.

Poster (2008, July)

Deficiency or inhibition of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism.

in Nature Genetics (2008), 40

HIF prolyl hydroxylases (PHD1-3) are oxygen sensors that regulate the stability of the hypoxia-inducible factors (HIFs) in an oxygen-dependent manner. Here, we show that loss of Phd1 lowers oxygen ... [more ▼]

HIF prolyl hydroxylases (PHD1-3) are oxygen sensors that regulate the stability of the hypoxia-inducible factors (HIFs) in an oxygen-dependent manner. Here, we show that loss of Phd1 lowers oxygen consumption in skeletal muscle by reprogramming glucose metabolism from oxidative to more anaerobic ATP production through activation of a Pparalpha pathway. This metabolic adaptation to oxygen conservation impairs oxidative muscle performance in healthy conditions, but it provides acute protection of myofibers against lethal ischemia. Hypoxia tolerance is not due to HIF-dependent angiogenesis, erythropoiesis or vasodilation, but rather to reduced generation of oxidative stress, which allows Phd1-deficient myofibers to preserve mitochondrial respiration. Hypoxia tolerance relies primarily on Hif-2alpha and was not observed in heterozygous Phd2-deficient or homozygous Phd3-deficient mice. Of medical importance, conditional knockdown of Phd1 also rapidly induces hypoxia tolerance. These findings delineate a new role of Phd1 in hypoxia tolerance and offer new treatment perspectives for disorders characterized by oxidative stress. [less ▲]

Tumoral and choroidal vascularization: differential cellular mechanisms involving plasminogen activator inhibitor type I.

in American Journal of Pathology (2007), 171(4), 1369-80

An adequate balance between serine proteases and their plasminogen activator inhibitor-1 (PAI-1) is critical for pathological angiogenesis. PAI-1 deficiency in mice is associated with impaired choroidal ... [more ▼]

An adequate balance between serine proteases and their plasminogen activator inhibitor-1 (PAI-1) is critical for pathological angiogenesis. PAI-1 deficiency in mice is associated with impaired choroidal neovascularization (CNV) and tumoral angiogenesis. In the present work, we demonstrate unexpected differences in the contribution of bone marrow (BM)-derived cells in these two processes regulated by PAI-1. PAI-1(-/-) mice grafted with BM-derived from wild-type mice were able to support laser-induced CNV formation but not skin carcinoma vascularization. Engraftment of irradiated wild-type mice with PAI-1(-/-) BM prevented CNV formation, demonstrating the crucial role of PAI-1 delivered by BM-derived cells. In contrast, the transient infiltration of tumor transplants by local PAI-1-producing host cells rather than by BM cells was sufficient to rescue tumor growth and angiogenesis in PAI-1-deficient mice. These data identify PAI-1 as a molecular determinant of a local permissive soil for tumor angiogenesis. Altogether, the present study demonstrates that different cellular mechanisms contribute to PAI-1-regulated tumoral and CNV. PAI-1 contributes to BM-dependent choroidal vascularization and to BM-independent tumor growth and angiogenesis. [less ▲]

Role of Gas-6 in adipogenesis and nutritionally induced adipose tissue development in mice.

in Arteriosclerosis, Thrombosis, and Vascular Biology (2005), 25(5), 1002-1007

OBJECTIVE: A potential role of growth arrest-specific gene 6 (Gas-6) in energy storage in adipose tissue was investigated in murine models of obesity. Gas-6 is a ligand for the Axl, C-Mer, and Sky family ... [more ▼]

OBJECTIVE: A potential role of growth arrest-specific gene 6 (Gas-6) in energy storage in adipose tissue was investigated in murine models of obesity. Gas-6 is a ligand for the Axl, C-Mer, and Sky family of tyrosine kinase receptors. METHODS AND RESULTS: Whereas Gas-6, C-Mer, and Sky were expressed in mature murine adipocytes, the expression of Axl was restricted to the stromal-vascular fraction, which includes pre-adipocytes. During the in vitro conversion of adipogenic 3T3-F442A cells into mature adipocytes, the expression of Gas-6 increased in undifferentiated confluent pre-adipocytes during a transient phase of growth arrest. On treatment of these cells with an adipogenic medium, Gas-6 expression decreased sharply, coinciding with expression of early adipocytes markers. This modulation was not observed in the nonadipogenic 3T3-C2 cells. The Gas-6 mRNA level was transiently downregulated during nutritionally induced expansion of adipose tissues in vivo. When kept on a standard diet, no significant difference in either total body weight or weight of gonadal or subcutaneous fat pads was observed between Gas-6 deficient and wild-type mice. On exposure to a high-fat diet, however, Gas-6-deficient mice had significantly less fat mass than their wild-type counterparts. CONCLUSIONS: Gas-6 enhances the accumulation of adipose tissue in diet-induced obese mice. [less ▲]

Dose-dependent modulation of choroidal neovascularization by plasminogen activator inhibitor type 1: Implications for clinical trials

in Investigative Ophthalmology & Visual Science (2003), 44(6), 2791-2797

PURPOSE. To explain the conflicting reports about the influence of plasminogen activator inhibitor type (PAI-1) on pathologic angiogenesis, such as occurs during the exudative form of age-related macular ... [more ▼]

PURPOSE. To explain the conflicting reports about the influence of plasminogen activator inhibitor type (PAI-1) on pathologic angiogenesis, such as occurs during the exudative form of age-related macular degeneration. METHODS. The expression of PAI-1 mRNA was analyzed in human and murine choroidal neovascularization (CNV) by RTPCR. The influences of increasing doses of recombinant PAI-1 were evaluated by daily intraperitoneal injections in PAI-1-1-and wild-type animals with a model of laser-induced CNV. The double mechanism of action of PAI-1 (proteolytic activity inhibition versus vitronectin binding) was explored by immunohistochemical localization of fibrinogen/fibrin and by injection of recombinant PAI-1 protein defective for vitronectin binding or with adenoviral vectors bearing a mutated binding-deficient PAI-1 gene. RESULTS. PAI-1 expression was present in human CNV and strongly induced in the course of experimental subretinal neovascularization. Daily injections of recombinant PAI-1 proteins in control and PAI-1(-/-) animals demonstrated that PAI-1 could exhibit both pro- and antiangiogenic effects, dependent on the dose. PAI-1 mutants defective for vitronectin binding were used to show that PAI-1 promotes choroidal pathologic angiogenesis merely through its antiproteolytic activity. CONCLUSIONS. These observations may help to reconcile reports with opposite results regarding the effects of PAI-1 on angiogenesis and certainly warn against uncontrolled use of PAL I modulating drugs in clinical trials. [less ▲]

Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions

in Nature Medicine (2001), 7(5), 575-583

Vascular endothelial growth factor (VEGF) stimulates angiogenesis by activating VEGF receptor-2 (VEGFR-2). The role of its homolog, placental growth factor (PlGF), remains unknown. Both VEGF and PlGF bind ... [more ▼]

Vascular endothelial growth factor (VEGF) stimulates angiogenesis by activating VEGF receptor-2 (VEGFR-2). The role of its homolog, placental growth factor (PlGF), remains unknown. Both VEGF and PlGF bind to VEGF receptor-1 (VEGFR-1), but it is unknown whether VEGFR-1, which exists as a soluble or a membrane-bound type, is an inert decoy or a signaling receptor for PlGF during angiogenesis. Here, we report that embryonic angiogenesis in mice was not affected by deficiency of PlGF (Pgf -/-). VEGF-B, another ligand of VEGFR-1, did not rescue development in Pgf -/- mice. However, loss of PlGF impaired angiogenesis, plasma extravasation and collateral growth during ischemia, inflammation, wound healing and cancer. Transplantation of wild-type bone marrow rescued the impaired angiogenesis and collateral growth in Pgf -/- mice, indicating that PlGF might have contributed to vessel growth in the adult by mobilizing bone-marrow−derived cells. The synergism between PlGF and VEGF was specific, as PlGF deficiency impaired the response to VEGF, but not to bFGF or histamine. VEGFR-1 was activated by PlGF, given that anti-VEGFR-1 antibodies and a Src-kinase inhibitor blocked the endothelial response to PlGF or VEGF/PlGF. By upregulating PlGF and the signaling subtype of VEGFR-1, endothelial cells amplify their responsiveness to VEGF during the 'angiogenic switch' in many pathological disorders. [less ▲]