Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Imatinib Disrupts Lymphoma Angiogenesis by Targeting Vascular Pericytes

ABSTRACT: Pericytes/vascular smooth muscle cells (VSMCs), regulated by platelet-derived growth factor receptor β (PDGFRβ) signaling, play important roles in endothelial survival and vascular stability. Here we report that treatment with imatinib, an inhibitor of PDGFRβ, led to significant tumor growth impairment associated with increased apoptosis in human lymphoma xenografts including Farage, Karpas422 and OCI-Ly7 in SCID mice. Confocal analysis of the tumor tissue showed decreased microvessel density, decreased vascular flow, and increased vascular leak in the imatinib-treated cohorts. Imatinib targeted tumor-associated PDGFRβ+ pericytes in vivo by inducing apoptosis and disruption of the PDGFRβ+ perivascular network, and PDGFRβ+ VSMC in vitro by inhibition of proliferation. FACS analysis of mononuclear cell suspension of tumor tissues revealed decreased mature pericytes and endothelial cells, as well as their progenitors with imatinib treatment. Compared to imatinib, treatment with anti-PDGFRβ monoclonal antibody partially inhibited the growth of Farage lymphomas. Lastly, microarray analysis of differentially expressed genes in PDGFRβ+ VSMC following imatinib treatment showed significant down-regulation of genes implicated in proliferation, survival and angiogenesis, including those within PI3K/AKT and MAPK/ERK1/2 pathways downstream of PDGFRβ signaling. Taken together, targeting PDGFRβ+ pericytes in lymphoma presents a novel and complementary target to endothelial cells for efficacious antiangiogenic therapy. PDGFRb+ murine vascular smooth muscle cells (VSMCs) were treated in 10 uM imatinib for 24 or 48 hours. Gene expression changes in response to imatinib treatment were examined using NimbleGen MM8_60mer gene expression microarrays by comparing expression patterns at 24- and 48-hours treatment to the baseline level (0 hours).

ORGANISM(S): Mus musculus

SUBMITTER: Huimin Geng

PROVIDER: E-GEOD-30752 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Vascular smooth muscle cell (VSMC) dysregulation is a hallmark of vascular disease, including atherosclerosis. In particular, the majority of cells within atherosclerotic lesions are generated from pre-existing VSMCs and a clonal nature has been documented for VSMC-derived cells in multiple disease models. However, the mechanisms underlying the generation of oligoclonal lesions and the phenotype of proliferating VSMCs are unknown.Here we analyse clonal dynamics in multi-color lineage-traced animals over time after vessel injury to understand the cellular mechanisms underlying clonal VSMC expansion in disease.We demonstrate that VSMC proliferation is initiated in a small fraction of VSMCs that initially expand clonally in the medial layer and then migrate to form the oligoclonal neointima. Selective activation of VSMC proliferation also occurs in vitro, suggesting that this is a cell-autonomous feature. Mapping of VSMC trajectories using single-cell RNA-sequencing reveals a continuum of cellular states after injury and suggests that VSMC proliferation initiates in cells that have downregulated the contractile phenotype and show evidence of pronounced phenotypic switching. We show that proliferation is associated with induced expression of stem cell antigen 1 (SCA1) and the expression signature previously identified in SCA1+ VSMCs in healthy arteries. A remarkably increased proliferation of SCA1+ VSMCs, directly validated in functional assays, indicates that SCA1+ VSMCs act as "first responders" in vascular injury. Early atherosclerotic lesions also had clonal VSMC contribution and we show that the proliferation-associated injury response is conserved in plaque VSMCs, extending these findings to atherosclerosis. Finally, we identify VSMCs in healthy human arteries that correspond to the SCA1+ state in mouse VSMCs and show that genes identified as differentially expressed in this human VSMC subpopulation are enriched for genes showing genetic association with cardiovascular disease. We show that cell-intrinsic, selective VSMC activation drives clonal proliferation after injury and in atherosclerosis. Our study suggests that healthy mouse and human arteries contain VSMCs characterised by expression of disease-associated genes that are predisposed for proliferation. Targeting such "first responder" cells in patients undergoing vascular surgery could effectively prevent injury-associated VSMC activation and neoatherosclerosis.

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Imatinib Disrupts Lymphoma Angiogenesis by Targeting Vascular Pericytes

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