Effects of PDGF-C and PDGF-D on monocyte migration and MMP-2 and MMP-9 expression

Wågsäter, Dick; Zhu, Changliang; Björck, Hanna M.; Eriksson, Per

doi:10.1016/j.atherosclerosis.2008.04.050

Cited by 75 publications

(56 citation statements)

References 29 publications

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“…Third, PDGF-CC inhibition reduced macrophages infiltration during CNV formation. Indeed, it is known that macrophages play important roles in pathological angiogenesis, and PDGF-CC is abundantly expressed by macrophages and promotes macrophage migration (18). Collectively, PDGF-CC inhibition has versatile effects on multiple cell types critical for pathological angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

PDGF-CC blockade inhibits pathological angiogenesis by acting on multiple cellular and molecular targets

Kumar

Lee

et al. 2010

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

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The importance of identifying VEGF-independent pathways in pathological angiogenesis is increasingly recognized as a result of the emerging drug resistance to anti-VEGF therapies. PDGF-CC is the third member of the PDGF family discovered after more than two decades of studies on PDGF-AA and PDGF-BB. The biological function of PDGF-CC and the underlying cellular and molecular mechanisms remain largely unexplored. Here, using different animal models, we report that PDGF-CC inhibition by neutralizing antibody, shRNA, or genetic deletion suppressed both choroidal and retinal neovascularization. Importantly, we revealed that PDGF-CC targeting acted not only on multiple cell types important for pathological angiogenesis, such as vascular mural and endothelial cells, macrophages, choroidal fibroblasts and retinal pigment epithelial cells, but also on the expression of other important angiogenic genes, such as PDGF-BB and PDGF receptors. At a molecular level, we found that PDGF-CC regulated glycogen synthase kinase (GSK)–3β phosphorylation and expression both in vitro and in vivo. Activation of GSK3β impaired PDGF-CC–induced angiogenesis, and inhibition of GSK3β abolished the antiangiogenic effect of PDGF-CC blockade. Thus, we identified PDGF-CC as an important candidate target gene for antiangiogenic therapy, and PDGF-CC inhibition may be of therapeutic value in treating neovascular diseases.

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Section: Discussionmentioning

confidence: 99%

PDGF-CC blockade inhibits pathological angiogenesis by acting on multiple cellular and molecular targets

Kumar

Lee

et al. 2010

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

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“…Several mechanisms underlie the antiangiogenic effect of PDGF-DD targeting. First, PDGF-DD is expressed by macrophages (13) and is a potent chemoattractant for them (18). It is known that macrophages play an important role in pathological angiogenesis (75).…”

Section: Discussionmentioning

confidence: 99%

“…PDGF-DD has also been shown to play an important role in inflammation, because PDGF-DD overexpression induced macrophage recruitment into the skin and skeletal muscles (16), whereas intracoronary PDGF-D gene transfer enhanced cardiac allograft inflammation (17). Indeed, PDGF-DD is expressed in macrophages and promoted monocyte migration in a dose-dependent manner (18). In addition, PDGF-DD contributes to tumor growth (19 -22).…”

mentioning

confidence: 99%

Platelet-derived Growth Factor-DD Targeting Arrests Pathological Angiogenesis by Modulating Glycogen Synthase Kinase-3β Phosphorylation

Kumar

Lee

et al. 2010

Journal of Biological Chemistry

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Platelet-derived growth factor-DD (PDGF-DD) is a recently discovered member of the PDGF family. The role of PDGF-DD in pathological angiogenesis and the underlying cellular and molecular mechanisms remain largely unexplored. In this study, using different animal models, we showed that PDGF-DD expression was up-regulated during pathological angiogenesis, and inhibition of PDGF-DD suppressed both choroidal and retinal neovascularization. We also demonstrated a novel mechanism mediating the function of PDGF-DD. PDGF-DD induced glycogen synthase kinase-3␤ (GSK3␤) Ser 9 phosphorylation and Tyr 216 dephosphorylation in vitro and in vivo, leading to increased cell survival. Consistently, GSK3␤ activity was required for the antiangiogenic effect of PDGF-DD targeting. Moreover, PDGF-DD regulated the expression of GSK3␤ and many other genes important for angiogenesis and apoptosis. Thus, we identified PDGF-DD as an important target gene for antiangiogenic therapy due to its pleiotropic effects on vascular and non-vascular cells. PDGF-DD inhibition may offer new therapeutic options to treat neovascular diseases.

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“…Tissue samples were homogenized with FastPrep using Lysing Matrix D tubes (MP Biomedicals, Illkirch, France). Total-RNA from tissue or cells in culture was isolated with RNeasy (Qiagen, Germany) and cDNA (1.0 ng) was amplified by RT-PCR reactions as described before (19). The following probe was used for analysis of human serpinA3 expression: Hs00153674 and murine serpinA3n expression: Mm00776439, and results were normalized to values of human RPLP0: Hs99999902 or murine β2 microglobulin: Mm00437762.…”

Section: Methodsmentioning

confidence: 99%

Serine protease inhibitor A3 in atherosclerosis and aneurysm disease

Wågsäter

Johansson

Fontaine

et al. 2012

International Journal of Molecular Medicine

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Abstract. Remodeling of extracellular matrix (ECM) plays an important role in both atherosclerosis and aneurysm disease. Serine protease inhibitor A3 (serpinA3) is an inhibitor of several proteases such as elastase, cathepsin G and chymase derived from mast cells and neutrophils. In this study, we investigated the putative role of serpinA3 in atherosclerosis and aneurysm formation. SerpinA3 was expressed in endothelial cells and medial smooth muscle cells in human atherosclerotic lesions and a 14-fold increased expression of serpinA3n mRNA was found in lesions from Apoe -/-mice compared to lesion-free vessels. In contrast, decreased mRNA expression (-80%) of serpinA3 was found in biopsies of human abdominal aortic aneurysm (AAA) compared to non-dilated aortas. Overexpression of serpinA3n in transgenic mice did not influence the development of atherosclerosis or CaCl 2 -induced aneurysm formation. In situ zymography analysis showed that the transgenic mice had lower cathepsin G and elastase activity, and more elastin in the aortas compared to wild-type mice, which could indicate a more stable aortic phenotype. Differential vascular expression of serpinA3 is clearly associated with human atherosclerosis and AAA but serpinA3 had no major effect on experimentally induced atherosclerosis or AAA development in mouse. However, serpinA3 may be involved in a phenotypic stabilization of the aorta.

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Effects of PDGF-C and PDGF-D on monocyte migration and MMP-2 and MMP-9 expression

Cited by 75 publications

References 29 publications

PDGF-CC blockade inhibits pathological angiogenesis by acting on multiple cellular and molecular targets

PDGF-CC blockade inhibits pathological angiogenesis by acting on multiple cellular and molecular targets

Platelet-derived Growth Factor-DD Targeting Arrests Pathological Angiogenesis by Modulating Glycogen Synthase Kinase-3β Phosphorylation

Serine protease inhibitor A3 in atherosclerosis and aneurysm disease

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