Heparan sulphate requirement in platelet-derived growth factor B-mediated pericyte recruitment

Kurup, Sindhulakshmi; Abramsson, Alexandra; Li, Jinping; Lindahl, Ulf; Kjellén, Lena; Betsholtz, Christer; Gerhardt, Holger; Spillmann, Dorothe

doi:10.1042/bst0340454

Cited by 11 publications

(8 citation statements)

References 9 publications

(9 reference statements)

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“…21 Endoglin has been identified as a candidate tumor suppressor gene in esophageal squamous cell carcinoma. 22 PDGFB is a mitogenic factor for mesenchymal cells, 23 and its loss is difficult to explain in leiomyoma-like areas. Perhaps other tumor suppressor genes are located in the vicinity of PDGFB, which is at 22q13.1.…”

Section: Discussionmentioning

confidence: 99%

Molecular and immunohistochemical evidence for the origin of uterine leiomyosarcomas from associated leiomyoma and symplastic leiomyoma-like areas

et al. 2009

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It is uncertain whether uterine leiomyosarcoma arises de novo or in preexisting leiomyoma. Leiomyoma-like areas can be seen associated with uterine leiomyosarcoma, raising the possibility of precursor lesions for uterine leiomyosarcoma. In this study, we examined cases of uterine leiomyosarcoma associated with leiomyoma-like areas at the histological, immunohistochemical and DNA level to further evaluate if benignlooking leiomyoma-like and uterine leiomyosarcoma areas are related. Cases of uterine leiomyosarcoma observed at the New York University Medical Center from 1994 to 2007 were reviewed for the presence of leiomyoma-like areas. Of the 26 cases of uterine leiomyosarcoma observed during this period, 18 cases had an associated leiomyoma-like area (five cellular leiomyoma, four symplastic leiomyoma, four cellular and symplastic leiomyoma and five usual type leiomyoma). Sixteen of the 18 cases were examined immunohistochemically for Ki-67, for estrogen receptor, progesterone receptor and for p53. Immunohistochemical profiles were as expected for leiomyoma-like (the mean expression of p53, ER, PR and Ki-67 at 0.3, 63, 75 and 0.6%, respectively), symplastic leiomyoma-like areas (the mean expression of p53, ER, PR and Ki-67 at 0.6, 85, 89 and 5.5%, respectively) and uterine leiomyosarcoma areas (the mean expression of p53, ER, PR and Ki-67 at 52, 38, 39 and 61%, respectively). In six cases, the leiomyoma-like and uterine leiomyosarcoma areas from each case were examined using high-density oligonucleotide array-CGH to determine genetic aberrations in the two areas. Nearly all the genetic aberrations found in leiomyoma-like areas were also found in the corresponding uterine leiomyosarcoma areas. In addition, uterine leiomyosarcoma areas had additional genetic aberrations. The immunohistochemical profiles and genetic aberrations of the examined cases suggest that uterine leiomyosarcoma could arise from the preexisting leiomyoma-like areas that often have a symplastic or cellular morphology.

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Section: Discussionmentioning

confidence: 99%

Molecular and immunohistochemical evidence for the origin of uterine leiomyosarcomas from associated leiomyoma and symplastic leiomyoma-like areas

et al. 2009

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“…Reduced N-sulfation impairs PDGF-BB binding and PDGFR-␤ signaling, leading to delayed PC recruitment and increased detachment. 1,12 Complete loss of N-sulfated HS in vascular structures growing from embryoid bodies ex vivo illustrated that VEGFR signaling requires HS as coreceptor during vascular morphogenesis. In the absence of endothelial HS, MC-derived N-sulfated HS is sufficient to support VEGFR signaling, illustrating that HS and VEGFR can interact in trans during this process.…”

Section: Discussionmentioning

confidence: 99%

“…This lack of phenotype stands in marked contrast to findings in mice deficient in PDGFR-␤ signaling, such as Pdgfrb Ϫ/Ϫ ( Figure 2V), the PDGF-B retention motif knockout, 11 and the Ndst1 Ϫ/Ϫ mice with a global reduction in N-sulfated HS. 1,12 Both the PDGF-B retention motif knockout and the Ndst1 Ϫ/Ϫ mice show defective PC recruitment resulting from absent or reduced ability of PDGF-BB to bind to HS. 1,12 To address whether the attached MCs in the EXT1 MCko indeed lack HS expression, we labeled the hindbrains with the 10E4 antibody ( Figure 2B,D,F,H-P).…”

Section: Ext1mentioning

confidence: 99%

“…1,12 Both the PDGF-B retention motif knockout and the Ndst1 Ϫ/Ϫ mice show defective PC recruitment resulting from absent or reduced ability of PDGF-BB to bind to HS. 1,12 To address whether the attached MCs in the EXT1 MCko indeed lack HS expression, we labeled the hindbrains with the 10E4 antibody ( Figure 2B,D,F,H-P). In control hindbrain samples, we detect HS in the endothelium as well as in MCs, particularly at the interface of ECs and MCs ( Figure 2C,D,I,M arrows).…”

Section: Ext1mentioning

confidence: 99%

“…Appropriate N-sulfation is required to retain PDGF-BB and to activate PDGFR-␤ in MCs in vivo. 1,12 Therefore, HSPGs are important coreceptors and activators of signaling events during MC recruitment.…”

Section: Introductionmentioning

confidence: 99%

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Peripheral mural cell recruitment requires cell-autonomous heparan sulfate

Stenzel

Nye

Nisancioglu

et al. 2009

Blood

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IntroductionTumor blood vessels have multiple structural and functional abnormalities. A characteristic of the tumor vasculature is the deficiency or loose attachment of mural cells (MCs), that is, vascular smooth muscle cells in arteries, arterioles, and veins and pericytes (PCs) in capillaries. In many pathologic processes, such as diabetic retinopathy, the absence and loss of PC coverage cause destabilization and subsequent regression of blood vessels as well as increased permeability resulting in an abnormal and leaky vasculature. 1,2 MCs are key players in vessel stabilization and maturation. MCs may contribute to the stability of the vessel by providing direct mechanical support, through matrix deposition and/or by the release, presentation and activation of signals that promote endothelial cell (EC) differentiation and quiescence. 3 Several ligand-receptor systems have been implicated in this process. Transforming growth factor-␤ (TGF-␤) regulates proliferation and differentiation of ECs and MCs 4 and mediates the de novo induction of MC from the mesenchymal cell lineage during embryonic development. 5 Ex vivo, TGF-␤ becomes active on close cell-cell contact, via gap junctions between MCs and ECs. 4 Recent studies also illustrate that components of the TGF-␤ pathway, including TGF-␤ receptors, interact and cocluster directly with VE-cadherin at EC-EC junctions, thereby promoting vessel stabilization and quiescence. 6 In addition, junction organization leads to changes in cell function, and cell-cell-contact regulates many genes implicated in cell growth, apoptosis, matrix, and cytoskeletal remodeling. 7 Detailed studies on mouse mutants demonstrated the fundamental importance of endothelial platelet-derived growth factor B (PDGF-B) signaling to PDGF receptor-␤ (PDGFR-␤) on MCs during the recruitment process. 8,9 Deletion of Pdgfb or Pdgfrb causes embryonic lethality resulting from vascular defects, including microaneurysms, vascular leakage, and hemorrhaging as a result of severe MC loss. 9 Conditional endothelial inactivation of Pdgfb illustrated that the endothelium provides the major source of PDGF-B required for migration and proliferation of MCs. PDGF-B protein is secreted by the endothelium as PDGF-BB homodimers. PDGF-BB binding to PDGFR-␤ on MCs leads to receptor dimerization and phosphorylation activating multiple downstream signaling pathways, including phosphoinositide 3-kinase and extracellular regulatory kinase 1/2 (Erk1/2) mitogen-activated protein kinase (MAPK), which stimulate migration and proliferation.PDGF-B contains a conserved C-terminal sequence of basic amino acids, a so-called retention motif that mediates binding to cell surface or extracellular matrix (ECM) heparan sulfate proteoglycan (HSPG). Mice deficient in the PDGF-B retention motif display vascular defects associated with PC detachment. Detailed studies on developmental and tumor angiogenesis led to the idea that heparan sulfate (HS) retains PDGF-BB close to the EC surface to facilitate directed MC migration along the sprout...

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Pericytes, the Mural Cells of the Microvascular System

Bergers

2008

Angiogenesis

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Heparan sulphate requirement in platelet-derived growth factor B-mediated pericyte recruitment

Cited by 11 publications

References 9 publications

Molecular and immunohistochemical evidence for the origin of uterine leiomyosarcomas from associated leiomyoma and symplastic leiomyoma-like areas

Molecular and immunohistochemical evidence for the origin of uterine leiomyosarcomas from associated leiomyoma and symplastic leiomyoma-like areas

Peripheral mural cell recruitment requires cell-autonomous heparan sulfate

Pericytes, the Mural Cells of the Microvascular System

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