Dataset Information

Oxidative stress-mediated thrombospondin-2 upregulation impairs bone marrow-derived angiogenic cell function in diabetes mellitus.

ABSTRACT: Circulating angiogenic cells play an essential role in angiogenesis but are dysfunctional in diabetes mellitus characterized by excessive oxidative stress. We hypothesize that oxidative stress-mediated upregulation of thrombospondin-2 (TSP-2), a potent antiangiogenic protein, contributes to diabetic bone marrow-derived angiogenic cell (BMAC) dysfunction.BMACs were isolated from adult male type 2 diabetic db/db mice and control db/+ (C57BLKS/J) mice. In Matrigel tube formation assay, angiogenic function was impaired in diabetic BMACs, accompanied by increased oxidative stress and nicotinamide adenine dinucleotide phosphate oxidase activity. BMAC angiogenic function was restored by overexpression of dominant negative Rac1 or by overexpression of manganese superoxide dismutase. TSP-2 mRNA and protein were both significantly upregulated in diabetic BMACs, mediated by increased oxidative stress as shown by a decrease in TSP-2 level after overexpression of dominant negative Rac1 or manganese superoxide dismutase. Silencing TSP-2 by its small interfering RNA in diabetic BMACs improved BMAC function in tube formation, adhesion, and migration assays. Notably, the upregulation of TSP-2 was also found in BMACs from streptozotocin-induced type 1 diabetic mice, and normal BMACs with high glucose treatment. let-7f, a microRNA which has been related to endothelial angiogenic function, is found to play key role in TSP-2 increase, but let-7f did not directly interact with TSP-2 mRNA.The upregulation of TSP-2 mediated by increased oxidative stress contributes to angiogenesis dysfunction in diabetic BMACs.

SUBMITTER: Bae ON

PROVIDER: S-EPMC3757565 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Oxidative stress-mediated thrombospondin-2 upregulation impairs bone marrow-derived angiogenic cell function in diabetes mellitus.

Bae Ok-Nam ON Wang Jie-Mei JM Baek Seung-Hoon SH Wang Qingde Q Yuan Hong H Chen Alex F AF

Arteriosclerosis, thrombosis, and vascular biology 20130530 8

<h4>Objective</h4>Circulating angiogenic cells play an essential role in angiogenesis but are dysfunctional in diabetes mellitus characterized by excessive oxidative stress. We hypothesize that oxidative stress-mediated upregulation of thrombospondin-2 (TSP-2), a potent antiangiogenic protein, contributes to diabetic bone marrow-derived angiogenic cell (BMAC) dysfunction.<h4>Approach and results</h4>BMACs were isolated from adult male type 2 diabetic db/db mice and control db/+ (C57BLKS/J) mice. ...[more]

PMID: 23723366

Similar Datasets

Project description:BackgroundDiabetes mellitus is a prevalent public health problem that affects about one-third of the US population and leads to serious vascular complications with increased risk for coronary artery disease. How bone marrow hematopoiesis contributes to diabetes mellitus complications is incompletely understood. We investigated the role of bone marrow endothelial cells in diabetic regulation of inflammatory myeloid cell production.MethodsIn 3 types of mouse diabetes mellitus, including streptozotocin, high-fat diet, and genetic induction using leptin-receptor-deficient db/db mice, we assayed leukocytes, hematopoietic stem and progenitor cells (HSPC). In addition, we investigated bone marrow endothelial cells with flow cytometry and expression profiling.ResultsIn diabetes mellitus, we observed enhanced proliferation of HSPC leading to augmented circulating myeloid cell numbers. Analysis of bone marrow niche cells revealed that endothelial cells in diabetic mice expressed less Cxcl12, a retention factor promoting HSPC quiescence. Transcriptome-wide analysis of bone marrow endothelial cells demonstrated enrichment of genes involved in epithelial growth factor receptor (Egfr) signaling in mice with diet-induced diabetes mellitus. To explore whether endothelial Egfr plays a functional role in myelopoiesis, we generated mice with endothelial-specific deletion of Egfr (Cdh5Cre Egfrfl/fl). We found enhanced HSPC proliferation and increased myeloid cell production in Cdh5Cre Egfrfl/fl mice compared with wild-type mice with diabetes mellitus. Disrupted Egfr signaling in endothelial cells decreased their expression of the HSPC retention factor angiopoietin-1. We tested the functional relevance of these findings for wound healing and atherosclerosis, both implicated in complications of diabetes mellitus. Inflammatory myeloid cells accumulated more in skin wounds of diabetic Cdh5Cre Egfrfl/fl mice, significantly delaying wound closure. Atherosclerosis was accelerated in Cdh5Cre Egfrfl/fl mice, leading to larger and more inflamed atherosclerotic lesions in the aorta.ConclusionsIn diabetes mellitus, bone marrow endothelial cells participate in the dysregulation of bone marrow hematopoiesis. Diabetes mellitus reduces endothelial production of Cxcl12, a quiescence-promoting niche factor that reduces stem cell proliferation. We describe a previously unknown counterregulatory pathway, in which protective endothelial Egfr signaling curbs HSPC proliferation and myeloid cell production.

Project description:IntroductionAngiotensin (Ang)-(1-7) is a recently identified vasoprotective heptapeptide, and it appears to activate the reparative functions of bone marrow-derived stem/progenitor cells (BMPCs).AimThis study evaluated the effect of Ang-(1-7) in the angiogenic function of cavernosum in type 1 diabetes (T1D) and delineated the role of BMPCs in this protective function.MethodsT1D was induced by streptozotocin in mice, and mice with 20-24 weeks of diabetes were used for the study. Ang-(1-7) was administered subcutaneously by using osmotic pumps. Cavernosa, and BMPCs from peripheral blood and bone marrow were evaluated in different assay systems.Main outcome measuresAngiogenic function was determined by endothelial tube formation in matrigel assay. Circulating BMPCs were enumerated by flow cytometry and proliferation was determined by BrdU incorporation. Cell-free supernatant of BMPCs were collected and tested for paracrine angiogenic effect. Expression of angiogenic factors in BMPCs and cavernosa were determined by real-time polymerase chain reaction.ResultsAng-(1-7) (100 nM) stimulated angiogenesis in mouse cavernosum that was partially inhibited by Mas1 receptor antagonist, A779 (10 μM) (P < 0.05). In cavernosa of T1D, the angiogenic responses to Ang-(1-7) (P < 0.005) and VEGF (100 nM) (P < 0.03) were diminished. Ang-(1-7) treatment for 4 weeks reversed T1D-induced decrease in the VEGF-mediated angiogenesis. Ang-(1-7) treatment increased the circulating number of BMPCs and proliferation that were decreased in T1D (P < 0.02). Paracrine angiogenic function of BMPCs was reduced in diabetic BMPCs, which was reversed by Ang-(1-7). In diabetic BMPCs, SDF and angiopoietin-1 were upregulated by Ang-(1-7), and in cavernosum, VEGFR1, Tie-2, and SDF were upregulated and angiopoietin-2 was down-regulated.ConclusionsAng-(1-7) stimulates angiogenic function of cavernosum in diabetes via its stimulating effects on both cavernosal microvasculature and BMPCs.

Dataset Information

Oxidative stress-mediated thrombospondin-2 upregulation impairs bone marrow-derived angiogenic cell function in diabetes mellitus.

Publications

Oxidative stress-mediated thrombospondin-2 upregulation impairs bone marrow-derived angiogenic cell function in diabetes mellitus.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets