scholarly journals The related FLT4, FLT1, and KDR receptor tyrosine kinases show distinct expression patterns in human fetal endothelial cells.

1993 ◽  
Vol 178 (6) ◽  
pp. 2077-2088 ◽  
Author(s):  
A Kaipainen ◽  
J Korhonen ◽  
K Pajusola ◽  
O Aprelikova ◽  
M G Persico ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Vascular Endothelial Cells ◽  
Expression Patterns ◽  
Vascular Endothelial ◽  
Vascular Permeability Factor ◽  
Kinase Gene ◽  
Permeability Factor

The growth factor receptors expressed on endothelial cells are of special interest because of their potential to program endothelial cell growth and differentiation during development and neovascularization in various pathological states, such as wound healing and angiogenesis associated with tumorigenesis. Vascular endothelial growth factor ([VEGF] also known as vascular permeability factor) is a potent mitogen and permeability factor, which has been suggested to play a role in embryonic and tumor angiogenesis. The newly cloned FLT4 receptor tyrosine kinase gene encodes a protein related to the VEGF receptors FLT1 and KDR/FLK-1. We have here studied the expression of FLT4 and the other two members of this receptor family in human fetal tissues by Northern and in situ hybridization. These results were also compared with the sites of expression of VEGF and the related placenta growth factor (PlGF). Our results reveal FLT4 mRNA expression in vascular endothelial cells in developing vessels of several organs. A comparison of FLT4, FLT1 and KDR/FLK-1 receptor mRNA signals shows overlapping, but distinct expression patterns in the tissues studied. Certain endothelia lack one or two of the three receptor mRNAs. These data suggest that the receptor tyrosine kinases encoded by the FLT gene family may have distinct functions in the regulation of the growth/differentiation of blood vessels.

scholarly journals Ultrastructural localization of vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) to the abluminal plasma membrane and vesiculovacuolar organelles of tumor microvascular endothelium.

1995 ◽  
Vol 43 (4) ◽  
pp. 381-389 ◽  
Author(s):  
Qu-Hong ◽  
J A Nagy ◽  
D R Senger ◽  
H F Dvorak ◽  
A M Dvorak
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Endothelial Cells ◽  
Plasma Membrane ◽  
Growth Factor ◽  
Vascular Permeability ◽  
Vascular Endothelial ◽  
Vascular Permeability Factor ◽  
Permeability Factor ◽  
Cytoplasmic Organelles ◽  
Endothelial Growth Factor

Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) is a cytokine secreted by many animal and human tumors, activated macrophages, keratinocytes, rheumatoid synovial cells, embryonic tissues, and by cultured epithelial and mesenchymal cell lines. It acts selectively on vascular endothelial cells to increase their permeability to circulating macromolecules and to stimulate their replication. Although not detectably expressed by vascular cells in the human and animal tumors we have studied, VPF/VEGF accumulates in the microvessels supplying tumors and certain inflammatory reactions in which VPF/VEGF is also overexpressed. Light microscopic immunohistochemistry lacked the resolution necessary to localize VPF/VEGF precisely in such vessels. Therefore, we used a pre-embedding immunocytochemical method to localize VPF/VEGF at the ultrastructural level in the new blood vessels that are elicited in the peritoneal walls of mice bearing a transplantable mouse ascites tumor of ovarian origin. Intense immunostaining for VPF/VEGF was observed on the abluminal plasma membrane of tumor-associated microvascular endothelial cells and in vesiculovacuolar organelles (VVOs) present in these same endothelial cells. (VVOs are recently described cytoplasmic organelles present in tumor vascular endothelium that provide an important pathway for extravasation of circulating macromolecules.) In contrast to labeling of the abluminal plasma membrane and VVO vesicles and vacuoles, endothelial cytoplasmic organelles, such as multivesicular bodies and Weibel-Palade bodies, and the underlying basal lamina, did not stain with antibodies to VPF/VEGF. The distribution of VPF/VEGF here described corresponds to that anticipated for high-affinity VFP/VEGF receptors, although binding of VPF/VEGF to other endothelial cell surface structures, such as plasma membrane proteoglycans, is also a possibility.

scholarly journals Overexpression of vascular permeability factor/vascular endothelial growth factor and its receptors in psoriasis.

1994 ◽  
Vol 180 (3) ◽  
pp. 1141-1146 ◽  
Author(s):  
M Detmar ◽  
L F Brown ◽  
K P Claffey ◽  
K T Yeo ◽  
O Kocher ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Endothelial Cells ◽  
Growth Factor ◽  
Vascular Permeability ◽  
Microvascular Endothelial Cells ◽  
Psoriatic Skin ◽  
Vascular Endothelial ◽  
Vascular Permeability Factor ◽  
Permeability Factor ◽  
Endothelial Growth Factor

Psoriatic skin is characterized by microvascular hyperpermeability and angioproliferation, but the mechanisms responsible are unknown. We report here that the hyperplastic epidermis of psoriatic skin expresses strikingly increased amounts of vascular permeability factor (VPF; vascular endothelial growth factor), a selective endothelial cell mitogen that enhances microvascular permeability. Moreover, two VPF receptors, kdr and flt-1, are overexpressed by papillary dermal microvascular endothelial cells. Transforming growth factor alpha (TGF-alpha), a cytokine that is also overexpressed in psoriatic epidermis, induced VPF gene expression by cultured epidermal keratinocytes. VPF secreted by TGF-alpha-stimulated keratinocytes was bioactive, as demonstrated by its mitogenic effect on dermal microvascular endothelial cells in vitro. Together, these findings suggest that TGF-alpha regulates VPF expression in psoriasis by an autocrine mechanism, leading to vascular hyperpermeability and angiogenesis. Similar mechanisms may operate in tumors and in healing skin wounds which also commonly express both VPF and TGF-alpha.

scholarly journals Reconciling VEGF With VPF: The Importance of Increased Vascular Permeability for Stroma Formation in Tumors, Healing Wounds, and Chronic Inflammation

2021 ◽  
Vol 9 ◽  
Author(s):  
Harold F. Dvorak
Keyword(s):  
Endothelial Cells ◽  
Connective Tissue ◽  
Vascular Permeability ◽  
Vascular Endothelial Cells ◽  
Inflammatory Diseases ◽  
Expression Patterns ◽  
Vascular Endothelial ◽  
Vascular Permeability Factor ◽  
Healing Wounds

It is widely believed that vascular endothelial growth factor (VEGF) induces angiogenesis by its direct mitogenic and motogenic actions on vascular endothelial cells. However, these activities are only detected when endothelial cells are cultured at very low (0.1%) serum concentrations and would not be expected to take place at the much higher serum levels found in angiogenic sites in vivo. This conundrum can be resolved by recalling VEGF’s original function, that of an extremely potent vascular permeability factor (VPF). In vivo VPF/VEGF increases microvascular permeability such that whole plasma leaks into the tissues where it undergoes clotting by tissue factor that is expressed on tumor and host connective tissue cells to deposit fibrin and generate serum. By providing tissue support and by reprogramming the gene expression patterns of cells locally, fibrin and serum can together account for the formation of vascular connective tissue stroma. In sum, by increasing vascular permeability, VPF/VEGF triggers the “wound healing response,” setting in motion a fundamental pathophysiological process that induces the mature stroma that is found not only in healing wounds but also in solid tumors and chronic inflammatory diseases. Once initiated by increased vascular permeability, this response may be difficult to impede, perhaps contributing to the limited success of anti-VEGF therapies in treating cancer.

VEGF regulates the mobilization of VEGFR2/KDR from an intracellular endothelial storage compartment

Blood ◽  
2006 ◽  
Vol 108 (8) ◽  
pp. 2624-2631 ◽  
Author(s):  
Alexandra Gampel ◽  
Lara Moss ◽  
Matt C. Jones ◽  
Val Brunton ◽  
Jim C. Norman ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Tyrosine Kinases ◽  
Intracellular Trafficking ◽  
Receptor Tyrosine Kinases ◽  
Significant Proportion ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Src Tyrosine Kinase ◽  
Endothelial Growth Factor

AbstractEndothelial cells respond to vascular endothelial growth factor (VEGF) to produce new blood vessels. This process of angiogenesis makes a critical contribution during embryogenesis and also in the response to ischemia in adult tissues. We have studied the intracellular trafficking of the major VEGF receptor KDR (VEGFR2). Unlike other related growth factor receptors, we find that a significant proportion of KDR is held in an endosomal storage pool within endothelial cells. We find that KDR can be delivered to the plasma membrane from this intracellular pool and that VEGF stimulates this recycling to the cell surface. KDR recycling appears to be distinct from the previously characterized Rab4- and Rab11-dependent pathways, but, instead, KDR+ recycling vesicles contain Src tyrosine kinase and VEGF-stimulated recycling requires Src activation. Taken together, these data show that intracellular trafficking of KDR is markedly different from other receptor tyrosine kinases and suggest that the regulation of KDR trafficking by VEGF provides a novel mechanism for controlling the sensitivity of endothelial cells to proangiogenic signals.

scholarly journals Cardiovascular ephrinB2 function is essential for embryonic angiogenesis

Development ◽  
2002 ◽  
Vol 129 (6) ◽  
pp. 1397-1410 ◽  
Author(s):  
Sebastian S. Gerety ◽  
David J. Anderson
Keyword(s):  
Endothelial Cells ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Vascular Endothelial Cells ◽  
Mesenchymal Cells ◽  
Vascular Endothelial ◽  
Vascular Cells ◽  
Ephb Receptor ◽  
Essential Function ◽  
Specific Deletion

EphrinB2, a transmembrane ligand of EphB receptor tyrosine kinases, is specifically expressed in arteries. In ephrinB2 mutant embryos, there is a complete arrest of angiogenesis. However, ephrinB2 expression is not restricted to vascular endothelial cells, and it has been proposed that its essential function may be exerted in adjacent mesenchymal cells. We have generated mice in which ephrinB2 is specifically deleted in the endothelium and endocardium of the developing vasculature and heart. We find that such a vascular-specific deletion of ephrinB2 results in angiogenic remodeling defects identical to those seen in the conventional ephrinB2 mutants. These data indicate that ephrinB2 is required specifically in endothelial and endocardial cells for angiogenesis, and that ephrinB2 expression in perivascular mesenchyme is not sufficient to compensate for the loss of ephrinB2 in these vascular cells.

scholarly journals Bmx Tyrosine Kinase Has a Redundant Function Downstream of Angiopoietin and Vascular Endothelial Growth Factor Receptors in Arterial Endothelium

2001 ◽  
Vol 21 (14) ◽  
pp. 4647-4655 ◽  
Author(s):  
Iiro Rajantie ◽  
Niklas Ekman ◽  
Kristiina Iljin ◽  
Elena Arighi ◽  
Yuji Gunji ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Endothelial Cells ◽  
Growth Factor ◽  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Growth Factor Receptors ◽  
Vascular Endothelial ◽  
Kinase Gene ◽  
Venae Cavae ◽  
Endothelial Growth Factor

ABSTRACT The Bmx gene, a member of the Tec tyrosine kinase gene family, is known to be expressed in subsets of hematopoietic and endothelial cells. In this study, mice were generated in which the first coding exon of the Bmx gene was replaced with thelacZ reporter gene by a knock-in strategy. The homozygous mice lacking Bmx activity were fertile and had a normal life span without an obvious phenotype. Staining of their tissues using β-galactosidase substrate to assess the sites ofBmx expression revealed strong signals in the endothelial cells of large arteries and in the endocardium starting between days 10.5 and 12.5 of embryogenesis and continuing in adult mice, while the venular endothelium showed a weak signal only in the superior and inferior venae cavae. Of the five known endothelial receptor tyrosine kinases tested, activated Tie-2 induced tyrosyl phosphorylation of the Bmx protein and both Tie-2 and vascular endothelial growth factor receptor 1 (VEGFR-1) stimulated Bmx tyrosine kinase activity. Thus, the Bmx tyrosine kinase has a redundant role in arterial endothelial signal transduction downstream of the Tie-2 and VEGFR-1 growth factor receptors.

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