Microarray analysis of blood microvessels from PDGF‐B and PDGF‐Rβ mutant mice identifies novel markers for brain pericytes

Bondjers, Cecilia; He, Liqun; Takemoto, Minoru; Norlin, Jenny; Asker, Noomi; Hellström, Mats; Lindahl, Per; Betsholtz, Christer

doi:10.1096/fj.05-4944fje

Cited by 175 publications

(156 citation statements)

References 78 publications

(90 reference statements)

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“…Our observation that PDGFRa expression was low in thymic perivascular cells of adult mouse is consistent with other studies showing that neural crest-derived cells within the parenchyma of the thymus downregulate the expression of PDGFRa, whereas they maintain PDGFRb expression (Foster et al 2008;Müller et al 2008). A similar downregulation of PDGFRa has also been observed during pericyte differentiation in the brain (Bondjers et al 2006). Migration of neural crests into the thymus during embryogenesis and their differentiation into perivascular cells has been demonstrated (Foster et al 2008;Müller et al 2008).…”

Section: Discussionsupporting

confidence: 92%

Localization of Mesenchymal Cells in Adult Mouse Thymus: Their Abnormal Distribution in Mice With Disorganization of Thymic Medullary Epithelium

Odaka

2008

J Histochem Cytochem.

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S U M M A R Y Thymic mesenchymal cells are known to be important for the development of the early fetal thymus into a functionally mature organ supporting T cell differentiation. We examined the expression of mesenchymal markers: pan-mesenchymal marker ER-TR7, desmin, a-smooth muscle actin (a-SMA), and a-and b-chain of platelet-derived growth factor receptor (PDGFRa, PDGFRb) in thymi of normal adult mice. Desmin and ER-TR7 revealed specific staining in the capsule, septa, and perivascular cells. Most perivascular cells highly expressed PDGFRb at the same levels as desmin. Low expression of PDGFRa was detected in the capsule, intralobular septa, and some perivascular cells of normal adult thymi. a-SMA, used to identify vascular smooth muscle cells, was detectable on arterioles and some large venules but not on capillaries. Thus, desmin, PDGFRa, and PDGFRb were localized in the capsule, septa, and perivascular cells in thymus of adult mouse, although there were differences in the expression level among these markers. On the other hand, the expression of mesenchymal markers was detectable in the region of the thymic medullary epithelium of lymphotoxin b receptor-deficient mice and plt/plt mice, indicating that mesenchymal cells were abnormally localized in the region. These results suggest that disorganization of the medullary epithelium may be accompanied by aberrant distribution of mesenchyme in adult mouse thymus. (J Histochem Cytochem 57:373-382, 2009)

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Section: Discussionsupporting

confidence: 92%

Localization of Mesenchymal Cells in Adult Mouse Thymus: Their Abnormal Distribution in Mice With Disorganization of Thymic Medullary Epithelium

Odaka

2008

J Histochem Cytochem.

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“…36,37 We analyzed expression of Eltd1, Gpr116, Ramp2, Slc9a3r2, Slc43a3, Rasip1 and Hig2;NM_023516 in wild-type and pdgfb Ϫ/Ϫ microvessels by RTQ-PCR, expecting that putative pericyte markers would be significantly down-regulated in the latter. 26,38 As shown in Figure 5B, none of these genes behaved as a pericyte transcript. Hig2;NM_023516 was downregulated in pdgfb Ϫ/Ϫ microvessels (0.7 fold-change; log 2 ratioϭ Ϫ0.53) but at much lower than expected for a genuine pericyte marker 26 Thus, Hig2;NM_023516 is either expressed in both endothelial cells and pericytes, or is positively regulated in endothelial cells by the presence of pericytes.…”

Section: Expression In Pericyte-deficient Microvesselsmentioning

confidence: 90%

“…26 Total RNA samples were obtained from individual adults or embryos. Real-time quantitative PCR (RTQ-PCR) was performed using a 7300 instrument (Applied Biosystems) and standard protocols and reagents.…”

Section: Isolation Of Microvascular Fragments Rtq-pcr and Transcripmentioning

confidence: 99%

Identification of a Core Set of 58 Gene Transcripts With Broad and Specific Expression in the Microvasculature

Wallgard

Larsson

et al. 2008

ATVB

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Objective-Pathological angiogenesis is an integral component of many diseases. Antiangiogenesis and vascular targeting are therefore promising new therapeutic principles. However, few endothelial-specific putative drug targets have been identified, and information is still limited about endothelial-specific molecular processes. Here we aimed at determining the endothelial cell-specific core transcriptome in vivo. Methods and Results-Analysis of publicly available microarray data identified a mixed vascular/lung cluster of 132 genes that correlated with known endothelial markers. Filtering against kidney glomerular/nonglomerular and brain vascular/nonvascular microarray profiles separated contaminating lung markers, leaving 58 genes with broad and specific microvascular expression. More than half of these have not previously been linked to endothelial functions or studied in detail before. The endothelial cell-specific expression of a selected subset of these, Eltd1, Gpr116, Ramp2, Slc9a3r2, Slc43a3, Rasip1, and NM_023516, was confirmed by real-time quantitative polymerase chain reaction and/or immunohistochemistry. Conclusions-We have used a combination of publicly available and own microarray data to identify 58 gene transcriptswith broad yet specific expression in microvascular endothelium. Most of these have unknown functions, but many of them are predicted to be cell surface expressed or implicated in cell signaling processes and should therefore be explored as putative microvascular drug targets.

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“…5 Similarly, the consequences of pericyte deficiency were examined in brain microvessels by microarray analysis in platelet derived growth factor-B-deficient mice. 6 In a study of human coronary artery segments isolated from explanted hearts of cardiac transplant patients, King et al 7 identified multiple effected gene pathways and further confirmed the microarray findings by immunohistochemical analysis of selected proteins. Downstream gene targets of nitric oxide (NO) have been detected by Bogdan et al 8 however, no studies have been conducted to elucidate the molecular consequences of nitric oxide deficiency.…”

mentioning

confidence: 85%

The Krebs Cycle and Mitochondrial Mass Are Early Victims of Endothelial Dysfunction

Addabbo

Ratliff

Park

et al. 2009

The American Journal of Pathology

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Endothelial cell dysfunction is associated with bioavailable nitric oxide deficiency and an excessive generation of reactive oxygen species. We modeled this condition by chronically inhibiting nitric oxide generation with subpressor doses of N G -monomethyl-Larginine (L-NMMA) in C57B6 and Tie-2/green fluorescent protein mouse strains. L-NMMA-treated mice exhibited a slight reduction in vasorelaxation ability , as well as detectable abnormalities in soluble adhesion molecules (soluble intercellular adhesion molecule-1 and vascular cellular adhesion molecule-1, and matrix metalloproteinase 9), which represent surrogate indicators of endothelial dysfunction. Proteomic analysis of the isolated microvasculature using 2-dimensional gel electrophoresis and matrixassisted laser desorption/ionization time-of-flight mass spectroscopy revealed abnormal expression of a cluster of mitochondrial enzymes, which was confirmed using immunodetection. Aconitase-2 and enoyl-CoA-hydratase-1 expression levels were decreased in L-NMMA-treated animals; this phenotype was absent in nitric oxide synthase-1 and -3 knockout mice. Depletion of aconitase-2 and enoyl-CoA-hydratase-1 resulted in the inhibition of the Krebs cycle and enhanced pyruvate shunting toward the glycolytic pathway. To assess mitochondrial mass in vivo, co-localization of green fluorescent protein and MitoTracker fluorescence was detected by intravital microscopy. Quantitative analysis of fluorescence intensity showed that L-NMMA-treated animals exhibited lower fluorescence of MitoTracker in microvascular endothelia as a result of reduced mitochondrial mass. These findings provide conclusive and unbiased evidence that mitochondriopathy represents an early manifestation of endothelial dysfunction, shifting cell metabolism toward "metabolic hypoxia" through the selective depletion of both aconitase-2 and enoyl-CoAhydratase-1. These findings may contribute to an early preclinical diagnosis of endothelial dysfunction. (Am J

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Microarray analysis of blood microvessels from PDGF‐B and PDGF‐Rβ mutant mice identifies novel markers for brain pericytes

Cited by 175 publications

References 78 publications

Localization of Mesenchymal Cells in Adult Mouse Thymus: Their Abnormal Distribution in Mice With Disorganization of Thymic Medullary Epithelium

Localization of Mesenchymal Cells in Adult Mouse Thymus: Their Abnormal Distribution in Mice With Disorganization of Thymic Medullary Epithelium

Identification of a Core Set of 58 Gene Transcripts With Broad and Specific Expression in the Microvasculature

The Krebs Cycle and Mitochondrial Mass Are Early Victims of Endothelial Dysfunction

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