Revascularization of ischemic tissues by PDGF-CC via effects on endothelial cells and their progenitors

Li, Xuri; Tjwa, Marc; Moons, Lieve; Fons, Pierre; Noël, Agnès; Ny, Annelii; Zhou, Jian; Lennartsson, Johan; Li, Hong; Luttun, Aernout; Pontén, Annica; Devy, Laetitia; Bouché, Ann; Oh, Hideyasu; Manderveld, Ann; Blacher, Silvia; Communi, David; Savi, Pierre; Bono, Françoise; Dewerchin, Mieke; Foidart, Jean‐Michel; Autiero, Monica; Herbert, Jean‐Marc; Collen, Désiré; Heldin, Carl‐Henrik; Eriksson, Ulf J.; Carmeliet, Peter

doi:10.1172/jci200419189

Cited by 6 publications

(9 citation statements)

References 42 publications

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“…The kringle-2 interacts with both the CUB and the growth factor domains of PDGF-CC, possibly allowing the hinge region to loop out and thus positioning the cleavage site such that the protease domain in tPA can cleave. The kringle-2 domain has been demonstrated to inhibit FGF-2-induced endothelial cell proliferation and migration (39,40), and recently PDGF-CC has been shown to have a direct stimulatory effect on endothelial cell migration (6). As FGF-2 up-2 U. Eriksson, unpublished observation.…”

Section: Discussionmentioning

confidence: 99%

“…It has also been shown that PDGF-CC can enhance delayed wound healing in diabetic mice (21) and revascularization of ischemic tissues (6), further emphasizing the therapeutic potentials of PDGF-CC. Clearly, it is of importance to determine the structural and regulatory requirements of PDGF-CC activation.…”

mentioning

confidence: 97%

“…The classical members of this family, PDGF-A and PDGF-B, have been intensively studied and are known to be important for connective tissue growth and maintenance, and overexpression has been observed in several pathological conditions, including malignancies and atherosclerosis (2). Since its discovery, PDGF-C has been shown to play a role in palate formation (3), fibrotic disease development (4,5), and angiogenesis (6,7). Recently a fourth member, PDGF-D, has been added to this family of growth factors (8,9).…”

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confidence: 99%

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Structural Requirements for Activation of Latent Platelet-derived Growth Factor CC by Tissue Plasminogen Activator

Fredriksson

Ehnman

Fieber

et al. 2005

Journal of Biological Chemistry

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Platelet-derived growth factor C (PDGF-C) is one of four members in the PDGF family of growth factors, which are known mitogens and survival factors for cells of mesenchymal origin. PDGF-C has a unique twodomain structure consisting of an N-terminal CUB and a conserved C-terminal growth factor domain that are separated by a hinge region. PDGF-C is secreted as a latent dimeric factor (PDGF-CC), which undergoes extracellular removal of the CUB domains to become a PDGF receptor ␣ agonist. Recently, the multidomain serine protease tissue plasminogen activator (tPA), a thrombolytic agent used for treatment of acute ischemic stroke, was shown to cleave and activate PDGF-CC. In this study we determine the molecular mechanism of tPA-mediated activation of PDGF-CC. Using various PDGF-CC and tPA mutants, we were able to demonstrate that both the CUB and the growth factor domains of PDGF-C, as well as the kringle-2 domain of tPA, are required for the interaction and cleavage to occur. We also show that Arg 231 in PDGF-C is essential for tPAmediated proteolysis and that the released "free" CUB domain of PDGF-C can act as a competitive inhibitor of the cleavage reaction. Furthermore, we studied how the PDGF-C/tPA axis is regulated in primary fibroblasts and found that PDGF-C expression is downregulated by hypoxia but induced by transforming growth factor (TGF)-␤ 1 treatment. Elucidating the regulation and the mechanism of tPA-mediated activation of PDGF-CC will advance our knowledge of the physiological function of PDGF-CC and tPA and may provide new therapeutic opportunities for thrombolytic and cardiovascular therapies.

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Section: Discussionmentioning

confidence: 99%

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confidence: 97%

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confidence: 99%

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Structural Requirements for Activation of Latent Platelet-derived Growth Factor CC by Tissue Plasminogen Activator

Fredriksson

Ehnman

Fieber

et al. 2005

Journal of Biological Chemistry

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“…However, despite clinical progress, recent reports have raised questions about potential adverse effects of anti-VEGF antibodies or its pharmacological inhibitors, as they may not only affect aberrant vessel outgrowth but also the normal vasculature (14,15,22) and may even induce permeability resembling VEGF stimulation in vivo (25). Other VEGF-and plateletderived growth factor-related proangiogenic ligands have (15,27,28,41), as well as direct intracellular targets of the VEGF propermeability pathway, such as Src kinase (39). In this context, we observed that in laser-induced retinal vasculature lesions, IL-8 expression is increased concomitantly with VEGF expression in the damaged and inflamed retinal regions.…”

Section: Discussionmentioning

confidence: 99%

A Role for a CXCR2/Phosphatidylinositol 3-Kinase γ Signaling Axis in Acute and Chronic Vascular Permeability

Gavard

et al. 2009

Molecular and Cellular Biology

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Most proangiogenic polypeptide growth factors and chemokines enhance vascular permeability, including vascular endothelial growth factor (VEGF), the main target for anti-angiogenic-based therapies, and interleukin-8 (IL-8), a potent proinflammatory mediator. Here, we show that in endothelial cells IL-8 initiates a signaling route that converges with that deployed by VEGF at the level of the small GTPase Rac1 and that both act through the p21-activated kinase to promote the phosphorylation and internalization of VE-cadherin. However, whereas VEGF activates Rac1 through Src-related kinases, IL-8 specifically signals to Rac1 through its cognate G protein-linked receptor, CXCR2, and the stimulation of the phosphatidylinositol 3-kinase ␥ (PI3K␥) catalytic isoform, thereby providing a specific molecular targeted intervention in vascular permeability. These results prompted us to investigate the potential role of IL-8 signaling in a mouse model for retinal vascular hyperpermeability. Importantly, we observed that IL-8 is upregulated upon laser-induced retinal damage, which recapitulates enhanced vascularization, leakage, and inflammatory responses. Moreover, blockade of CXCR2 and PI3K␥ was able to limit neovascularization and choroidal edema, as well as macrophage infiltration, therefore contributing to reduce retinal damage. These findings indicate that the CXCR2 and PI3K␥ signaling pathway may represent a suitable target for the development of novel therapeutic strategies for human diseases characterized by vascular leakage.During embryonic development, blood vessels arise from endothelial precursors which share their origin with hematopoietic precursors (8). These progenitors assemble into a primitive vascular network of small capillaries, through a process called vasculogenesis, and this vascular plexus progressively expands and remodels into a highly organized pattern by the growth of blood vessels from preexisting ones, a process referred to as angiogenesis (8). During adulthood, endothelial cells that form the vascular wall retain their plasticity and can be engaged in neovascularization in response to physiological stimuli, such as hypoxia, wound healing, and tissue repair. In addition, numerous human diseases and pathological conditions are characterized by an excessive, uncontrolled, and aberrant angiogenesis (35). This physiological process is often co-opted by tumor cells to build a new vascular network dedicated to supply oxygen and nutrients to the cancerous cells, thereby enabling them to proliferate and metastasize (16).Aberrant angiogenesis occurs in numerous pathological conditions, such as in acute and chronic inflammation, thrombotic reactions, edema, tumor-induced angiogenesis, and metastasis (35). For example, this process is central to the progression of many ocular diseases, where blood vessels show a disorganized and anarchic pattern and are frequently leaky (17). Indeed, the breakdown of the endothelial barrier, characterized by an uncontrolled increase in vascular permeability, contributes to...

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“…Thus, PDGFs, and particularly PDGF-BB, are important arteriogenic factors for stabilization of the newly formed vasculature. PDGFR-␣ is also expressed in blood-vessel endothelial cells (34). The rationale of our present work is to combine arteriogenic factors, such as PDGF-BB, with angiogenic factors, such as FGF-2, for therapeutic evaluation in a pig myocardial infarction model.…”

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confidence: 99%

Combinatorial protein therapy of angiogenic and arteriogenic factors remarkably improves collaterogenesis and cardiac function in pigs

Lu¹,

Xu²,

Zhang³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Establishment of functional and stable collaterals in the ischemic myocardium is crucial to restoring cardiac function after myocardial infarction. Here, we show that only dual delivery of a combination of angiogenic and arteriogenic factors to the ischemic myocardium could significantly reestablish stable collateral networks and improve myocardial perfusion and function. A combination of FGF-2 with PDGF-BB, two factors primarily targeting endothelial cells and vascular smooth muscle cells, remarkably promotes myocardial collateral growth and stabilizes the newly formed collateral networks, which significantly restore myocardial perfusion and function. Using various members of the PDGF family together with FGF-2 in an angiogenesis assay, we demonstrate that PDGFR-␣ is mainly involved in angiogenic synergism, whereas PDGFR-␤ mediates vessel stability signals. Our findings provide conceptual guidelines for the clinical development of proangiogenic/arteriogenic factors for the treatment of ischemic heart disease.angiogenesis ͉ growth factor ͉ ischemia ͉ myocardial infarction ͉ neovascularization A therosclerosis-induced coronary artery disease is the leading cause of morbidity and mortality in Western societies and increases at an alarming rate in developing countries (1). Usually, progressive atherosclerosis results in plaque rupture and thrombosis of major coronary arteries, leading to angina, myocardial infarction, and heart failure (2). Except for surgical interventions, an effective therapeutic method for treatment has been lacking. Although delivery of proangiogenic factors to the ischemic myocardium to stimulate collaterogenesis and to improve myocardial perfusion and function is a straightforward idea proposed for Ͼ30 years, clinical evaluation of these individual proangiogenic molecules has produced unfulfilled promises (3-5). After more than a decade of clinical practice with different single proangiogenic factors for the treatment of ischemic disorders, almost all large randomized, double-blinded, and placebo-controlled human trials have proven to be nonbeneficial (6-8).The clinical failures with this attractive approach have raised several unresolved fundamental issues regarding the basic mechanisms of cardiovascular biology. These include the underlying mechanisms of angiogenesis versus arteriogenesis, choice of proangiogenic agents, monotherapy versus combinatorial therapy, appropriate animal models for preclinical evaluation, optimal drug release systems, and time line of delivery. For improvement of perfusion of high-oxygenated blood in ischemic tissues, it is essential to reestablish functional arterial vascular networks, which should remain stable long-term. Most previous preclinical and clinical studies on the development of proangiogenic therapies for treating ischemic myocardium have been based on monotherapeutic approaches (9-20). These approaches usually lack rationales for understanding the molecular mechanisms of arteriogenesis, for defining molecular targets of the deliverable proangiogeni...

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Revascularization of ischemic tissues by PDGF-CC via effects on endothelial cells and their progenitors

Cited by 6 publications

References 42 publications

Structural Requirements for Activation of Latent Platelet-derived Growth Factor CC by Tissue Plasminogen Activator

Structural Requirements for Activation of Latent Platelet-derived Growth Factor CC by Tissue Plasminogen Activator

A Role for a CXCR2/Phosphatidylinositol 3-Kinase γ Signaling Axis in Acute and Chronic Vascular Permeability

Combinatorial protein therapy of angiogenic and arteriogenic factors remarkably improves collaterogenesis and cardiac function in pigs

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