scholarly journals Vasculogenesis and Angiogenesis in VEGF Receptor-1 Deficient Mice

2015 ◽  
pp. 161-176 ◽  
Author(s):  
Vivienne C. Ho ◽  
Guo-Hua Fong
Keyword(s):  
Vegf Receptor ◽  
Vasculogenesis And Angiogenesis ◽  
Deficient Mice

Neuropilin-1 on hematopoietic cells as a source of vascular development

Blood ◽  
2003 ◽  
Vol 101 (5) ◽  
pp. 1801-1809 ◽  
Author(s):  
Yoshihiro Yamada ◽  
Yuichi Oike ◽  
Hisao Ogawa ◽  
Yasuhiro Ito ◽  
Hajime Fujisawa ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Fetal Liver ◽  
Vascular Development ◽  
Hematopoietic Cells ◽  
Vegf Receptor ◽  
Knock Out ◽  
Neuropilin 1 ◽  
Vasculogenesis And Angiogenesis

Neuropilin-1 (NP-1) is a receptor for vascular endothelial growth factor-165 (VEGF165) and acts as a coreceptor that enhances the function of VEGF165 through VEGF receptor-2 (VEGFR-2). Studies using transgenic and knock-out mice of NP-1 indicated that this molecule is important for vascular development as well as neuronal development. We recently reported that clustered soluble NP-1 phosphorylates VEGFR-2 on endothelial cells with a low dose of VEGF165 and rescues the defective vascularity of the NP-1−/− embryo in vitro and in vivo. Here we show that NP-1 is expressed by CD45+ hematopoietic cells in the fetal liver, can bind VEGF165, and phosphorylates VEGFR-2 on endothelial cells. CD45+NP-1+ cells rescued the defective vasculogenesis and angiogenesis in the NP-1−/− P-Sp (para-aortic splanchnopleural mesodermal region) culture, although CD45+NP-1− cells did not. Moreover, CD45+NP-1+ cells together with VEGF165 induced angiogenesis in an in vivo Matrigel assay and cornea neovascularization assay. The extracellular domain of NP-1 consists of “a,” “b,” and “c” domains, and it is known that the “a” and “c” domains are necessary for dimerization of NP-1. We found that both the “a” and “c” domains are essential for such rescue of defective vascularities in the NP-1 mutant. These results suggest that NP-1 enhances vasculogenesis and angiogenesis exogenously and that dimerization of NP-1 is important for enhancing vascular development. In NP-1−/− embryos, vascular sprouting is impaired at the central nervous system (CNS) and pericardium where VEGF is not abundant, indicating that NP-1–expressing cells are required for normal vascular development.

Exogenous clustered neuropilin 1 enhances vasculogenesis and angiogenesis

Blood ◽  
2001 ◽  
Vol 97 (6) ◽  
pp. 1671-1678 ◽  
Author(s):  
Yoshihiro Yamada ◽  
Nobuyuki Takakura ◽  
Hirofumi Yasue ◽  
Hisao Ogawa ◽  
Hajime Fujisawa ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Low Dose ◽  
Vascular Development ◽  
Vegf Receptor ◽  
Wild Type ◽  
Flag Epitope ◽  
Neuropilin 1 ◽  
Vasculogenesis And Angiogenesis

Neuropilin 1 (NP-1) is a receptor for vascular endothelial growth factor (VEGF) 165 (VEGF165) and acts as a coreceptor that enhances VEGF165 function through tyrosine kinase VEGF receptor 2 (VEGFR-2). Transgenic overexpression of np-1results in an excess of capillaries and blood vessels and a malformed heart. Thus, NP-1 may have a key role in vascular development. However, how NP-1 regulates vascular development is not well understood. This study demonstrates how NP-1 can regulate vasculogenesis and angiogenesis in vitro and in vivo. In homozygous np-1mutant (np-1−/−) murine embryos, vascular sprouting was impaired in the central nervous system and pericardium. Para-aortic splanchnopleural mesoderm (P-Sp) explants fromnp-1−/− mice also had vascular defects in vitro. A monomer of soluble NP-1 (NP-1 tagged with Flag epitope) inhibited vascular development in cultured wild-type P-Sp explants by sequestering VEGF165. In contrast, a dimer of soluble NP-1 (NP-1 fused with the Fc part of human IgG) enhanced vascular development in cultured wild-type P-Sp explants. Moreover, the NP-1–Fc rescued the defective vascular development in culturednp-1−/− P-Sp explants. A low dose of VEGF alone did not promote phosphorylation of VEGFR-2 on endothelial cells from np-1−/− embryos, but simultaneous addition of a low dose of VEGF and NP-1–Fc phosphorylated VEGFR-2 significantly. Moreover, NP-1–Fc rescued the defective vascularity of np-1−/− embryos in vivo. These results suggest that a dimer form of soluble NP-1 delivers VEGF165 to VEGFR-2–positive endothelial cells and promotes angiogenesis.

scholarly journals DNA Vaccination Against VEGF Receptor 2 Reduces Atherosclerosis in LDL Receptor–Deficient Mice

2007 ◽  
Vol 27 (5) ◽  
pp. 1095-1100 ◽  
Author(s):  
Ramona J. Petrovan ◽  
Charles D. Kaplan ◽  
Ralph A. Reisfeld ◽  
Linda K. Curtiss
Keyword(s):  
Ldl Receptor ◽  
Dna Vaccination ◽  
Vegf Receptor ◽  
Deficient Mice

scholarly journals VEGF receptor 1 signaling is essential for osteoclast development and bone marrow formation in colony-stimulating factor 1-deficient mice

2005 ◽  
Vol 102 (39) ◽  
pp. 14016-14021 ◽  
Author(s):  
S. Niida ◽  
T. Kondo ◽  
S. Hiratsuka ◽  
S.-I. Hayashi ◽  
N. Amizuka ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Vegf Receptor ◽  
Colony Stimulating Factor ◽  
Stimulating Factor ◽  
Deficient Mice

Abstract 916: Klotho-protein Regulates Transient Receptor Potential Canonical-1-mediated Ca(2+)-influx In Endothelial Cells And Prevents Cell Death And Disruption Of Endothelial Integrity Induced By Ca(2+)-overload

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Mitsuhiko Okigaki ◽  
Tetsurou Kusaba ◽  
Shoken Honsho ◽  
Akihiro Matsui ◽  
Shinsaku Matsunaga ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Vascular Calcification ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Peak Level ◽  
Vegf Receptor ◽  
Downstream Signaling ◽  
Klotho Protein ◽  
Deficient Mice

Introduction Klotho-deficient mice have extensive vascular calcification. However, the mechanism involved has not been elucidated. We analyzed the endothelial cells of Klotho-deficient mice (Klotho-ECs) and found a novel functional role for the Klotho-protein in the maintenance of vascular homeostasis. Methods and Results Primary-cultured endothelial cells from the aorta of wild-type- (WT) and Klotho- deficient mice were loaded with fura-2 and stimulated with VEGF. In WT-ECs, intracellular Ca(2+) concentration ([Ca(2+)]i) elevated to the peak level, and it decreased to the basal level in +5 minutes. Whereas, in Klotho-ECs, after similar peak level to WT-ECs, the elevation of [Ca(2+)]i was sustained at ~35% of the peak level for more than 10 minutes. In Ca(2+) free medium, this sustained elevation was abolished. Immunostaining revealed that, in Klotho-ECs, VEGF-induced co-internalization of the Ca(2+) channel; TRPC-1, with VEGF-receptor-2 (VEGFR-2) was abolished, thereby, at 30 minutes after VEGF-stimulation, expression levels of TRPC-1 in the plasmamembrane was 2.2-fold higher than in WT-ECs. Klotho-protein constitutively bound to VEGFR-2 and TRPC-1, strengthened their association, and promoted their co-internalization. VEGF-induced activation of Rac-1 and reorganization of F-actin, which are involved in internalization, were impaired in Klotho-ECs, and restored by the replacement of Klotho-protein. VEGF-induced phosphorylation of VEGFR-2 and its downstream signaling molecules, including Src, Akt, PLCγ, and Caveolin1, was attenuated. As the biological consequence of sustained increase in [Ca(2+)]i, activation of calpain and caspase-3 followed by apoptosis was promoted in Klotho-ECs in vivo and vitro. Also, expression of VE-cadherin in the plasmamembrane was reduced and intimal hyperpermeability was observed in the aorta of Klotho-deficient mice, which presumably lead to exudation of the Ca(2+)/phosphor -rich serum into the vessel walls, followed by extensive vascular calcification. Conclusion Thus, Klotho-protein regulates ligand-induced Ca(2+) influx and subsequent biological functions involved in vascular calcification.

scholarly journals Membrane Fixation of Vascular Endothelial Growth Factor Receptor 1 Ligand-Binding Domain Is Important for Vasculogenesis and Angiogenesis in Mice

2005 ◽  
Vol 25 (1) ◽  
pp. 346-354 ◽  
Author(s):  
Sachie Hiratsuka ◽  
Kazuki Nakao ◽  
Kenji Nakamura ◽  
Motoya Katsuki ◽  
Yoshiro Maru ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Endothelial Cells ◽  
Growth Factor ◽  
Tyrosine Kinase ◽  
Ligand Binding ◽  
Early Embryogenesis ◽  
Vascular Endothelial ◽  
Vasculogenesis And Angiogenesis ◽  
Endothelial Growth Factor ◽  
Deficient Mice

ABSTRACT Vascular endothelial growth factor (VEGF) regulates vasculogenesis and angiogenesis by using two tyrosine kinase receptors, VEGFR1 and VEGFR2. VEGFR1 null mutant mice die on embryonic day 8.5 (E8.5) to E9.0 due to an overgrowth of endothelial cells and vascular disorganization, suggesting that VEGFR1 plays a negative role in angiogenesis. We previously showed that the tyrosine kinase (TK) domain of VEGFR1 is dispensable for embryogenesis, since VEGFR1 TK-deficient mice survived and were basically healthy. However, the molecular basis for this is not yet clearly understood. To test the hypothesis that the specific role of VEGFR1 during early embryogenesis is to recruit its ligand to the cell membrane, we deleted the transmembrane (TM) domain in TK-deficient VEGFR1 mice. Surprisingly, about half of the VEGFR1(TM-TK)-deficient mice succumbed to embryonic lethality due to a poor development of blood vessels, whereas other mice were healthy. In VEGFR1(TM-TK)−/− mice with growth arrest, membrane-targeted VEGF was reduced, resulting in the suppression of VEGFR2 phosphorylation. Furthermore, the embryonic lethality in VEGFR1(TM-TK)−/− mice was significantly increased to 80 to 90% when the genotype of VEGFR2 was changed from homozygous (+/+) to heterozygous (+/−) in 129/C57BL6 mice. These results strongly suggest that the membrane-fixed ligand-binding region of VEGFR1 traps VEGF for the appropriate regulation of VEGF signaling in vascular endothelial cells during early embryogenesis.

Comparison of localization of metallothionein in tissues of metallothionein-deficient mice

1995 ◽  
Vol 53 ◽  
pp. 1042-1043
Author(s):  
H. Nishimura ◽  
R Nishimura ◽  
D.L. Adelson ◽  
A.E. Michaelska ◽  
K.H.A. Choo ◽  
...  
Keyword(s):  
Metal Binding ◽  
Immunohistochemical Staining ◽  
Squamous Epithelium ◽  
Rabbit Antiserum ◽  
Slight Modification ◽  
Positive Control ◽  
Heavy Metal Binding ◽  
Critical Organ ◽  
Metal Binding Protein ◽  
Deficient Mice

Metallothionein (MT), a cysteine-rich heavy metal binding protein, has several isoforms designated from I to IV. Its major isoforms, I and II, can be induced by heavy metals like cadmium (Cd) and, are present in various organs of man and animals. Rodent testes are a critical organ to Cd and it is still a controversial matter whether MT exists in the testis although it is clear that MT is not induced by Cd in this tissue. MT-IV mRNA was found to localize within tongue squamous epithelium. Whether MT-III is present mainly glial cells or neurons has become a debatable topic. In the present study, we have utilized MT-I and II gene targeted mice and compared MT localization in various tissues from both MT-deficient mice and C57Black/6J mice (C57BL) which were used as an MT-positive control. For MT immunostaining, we have used rabbit antiserum against rat MT-I known to cross-react with mammalian MT-I and II and human MT-III. Immunohistochemical staining was conducted by the method described in the previous paper with a slight modification after the tissues were fixed in HistoChoice and embedded in paraffin.

Alterations during Positive Selection in the Thymus of nackt CD4-Deficient Mice

2000 ◽  
Vol 52 (6) ◽  
pp. 555-562 ◽  
Author(s):  
I. Nepomnaschy ◽  
G. Lombardi ◽  
P. Bekinschtein ◽  
P. Berguer ◽  
V. Francisco ◽  
...  
Keyword(s):  
Positive Selection ◽  
Deficient Mice
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