Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

FLK-1/vascular endothelial growth factor receptor 2 (VEGFR-2) is one of the receptors for VEGF. In this study we examined the effect of cell density on activation of VEGFR-2. VEGF induces only very slight tyrosine phosphorylation of VEGFR-2 in confluent (95-100% confluent) pig aortic endothelial (PAE) cells. In contrast, robust VEGF-dependent tyrosine phosphorylation of VEGFR-2 was observed in cells plated in sparse culture conditions (60-65% confluent). A similar cell density-dependent phenomenon was observed in different endothelial cells but not in NIH-3T3 fibroblast cells expressing VEGFR-2. Stimulating cells with high concentrations of VEGF or replacing the extracellular domain of VEGFR-2 with that of the colony-stimulating factor 1 receptor did not alleviate the sensitivity of VEGFR-2 to cell density, indicating that the confluent cells were probably not secreting an antagonist to VEGF. Furthermore, in PAE cells, ectopically introduced platelet-derived growth factor alpha receptor could be activated at both high and low cell density conditions, indicating that the density effect was not universal for all receptor tyrosine kinases expressed in endothelial cells. In addition to lowering the density of cells, removing divalent cations from the medium of confluent cells potentiated VEGFR-2 phosphorylation in response to VEGF. These findings suggested that cell-cell contact may be playing a role in regulating the activation of VEGFR-2. To this end, pretreatment of confluent PAE cells with a neutralizing anti-cadherin-5 antibody potentiated the response of VEGFR-2 to VEGF. Our data demonstrate that endothelial cell density plays a critical role in regulating VEGFR-2 activity, and that the underlying mechanism appears to involve cadherin-5.
Mol Biol Cell 1999 Oct
PMID:A role for cadherin-5 in regulation of vascular endothelial growth factor receptor 2 activity in endothelial cells. 1051 75

We have examined the expression of the ovine clusterin gene in the sheep pituitary gland, with the aim of determining its site of synthesis in this tissue. Northern blotting analysis of extracted polyadenylated RNA, using a (32)P-labelled rat clusterin cDNA probe, detected the greatest amounts of clusterin mRNA in the anterior part of dissected pituitary glands. In situ hybridisation studies showed clusterin mRNA in anterior and intermediate pituitary cells, with lower amounts in vascular endothelium and posterior pituicytes. Clusterin protein, detected by immunohistochemistry, was observed in some single secretory cells, within the capillary lumen and in cells around capillaries in the anterior and intermediate lobes, but no immunoreactivity was observed in posterior pituitary tissue. The pattern of clusterin expression in anterior and intermediate pituitary cells suggests possible roles for the protein in secretory cell turnover and/or hormone secretion or lipid uptake. Clusterin does not appear to be involved in ovine posterior pituitary hormone neurosecretion.
J Mol Endocrinol 1999 Oct
PMID:Clusterin is expressed in the anterior and intermediate lobes, but not in the posterior pituitary of sheep. 1051 57

ENDOGLIN codes for a homodimeric membrane glycoprotein that interacts with receptors for members of the TGF-beta superfamily and is the gene mutated in the autosomal dominant vascular disorder hereditary hemorrhagic telangiectasia type 1 (HHT1). We recently demonstrated that functional endoglin was expressed at half levels on human umbilical vein endothelial cells (HUVECs) and peripheral blood activated monocytes from HHT1 patients. Two types of mutant protein were previously analyzed, the product of an exon 3 skip which was expressed as a transient intracellular species and prematurely truncated proteins that were undetectable in patient samples. Here we report the analysis of four proteins resulting from point mutations, with missense codons G52V and C53R in exon 2, W149C in exon 4 and L221P in exon 5. Metabolic labeling of activated monocytes from confirmed, clinically affected patients revealed reduced expression of fully processed normal endoglin in all cases. Pulse-chase analysis with HUVECs from a newborn with the C53R substitution indicated that mutant endoglin remained intracellular as a precursor form and did not impair processing of the normal protein. Biotinylation of cell surface proteins, metabolic labeling and pulse-chase analysis revealed that none of the engineered missense mutants was significantly expressed at the surface of COS-1 transfectants. Thus, these four HHT1 missense mutations lead to transient intracellular species which cannot interfere with normal endoglin function. These data suggest that haploinsufficiency, leading to reduced levels of one of the major surface glyco-proteins of vascular endothelium, is the predominant mechanism underlying the HHT1 phenotype.
Hum Mol Genet 1999 Nov
PMID:Expression analysis of four endoglin missense mutations suggests that haploinsufficiency is the predominant mechanism for hereditary hemorrhagic telangiectasia type 1. 1054 96

Endothelial nitric oxide (NO) synthase (eNOS) produces NO, which contributes to vascular reactivity in the fetal lung. Pulmonary vasoreactivity develops during late gestation in the ovine fetal lung, during the period of rapid capillary and alveolar growth. Although eNOS expression peaks near birth in the fetal rat, lung capillary and distal air space development occur much later than in the fetal lamb. To determine whether lung eNOS expression in the lamb differs from the timing and pattern reported in the rat, we measured eNOS mRNA and protein by Northern and Western blot analyses and NOS activity by the arginine-to-citrulline conversion assay in lung tissue from fetal, newborn, and maternal sheep. Cellular localization of eNOS expression was determined by immunohistochemistry. eNOS mRNA, protein, and activity were detected in samples from all ages, and eNOS was expressed predominantly in the vascular endothelium. Lung eNOS mRNA expression increases from low levels at 70 days gestation to peak at 113 days and remains high for the rest of fetal life. Newborn eNOS mRNA expression does not change from fetal levels but is lower in the adult ewe. Lung eNOS protein expression in the fetus rises and peaks at 118 days gestation but decreases before birth. eNOS protein expression rises in the newborn period but is lower in the adult. Lung NOS activity also peaks at 118 days gestation in the fetus before falling in late gestation and remaining low in the newborn and adult. We conclude that the pattern of lung eNOS expression in the sheep differs from that in the rat and may reflect species-related differences in lung development. We speculate that the rise in fetal lung eNOS may contribute to the marked lung growth and angiogenesis that occurs during the same period of time.
Am J Physiol Lung Cell Mol Physiol 2000 Jan
PMID:Developmental changes in endothelial nitric oxide synthase expression and activity in ovine fetal lung. 1064 8

Intercellular adhesion molecule-1 (ICAM-1) of the vascular endothelium plays a key role in the development of pulmonary oxygen toxicity. We studied the effect of steroid on hyperoxia-induced ICAM-1 expression using cultured endothelial cells in vitro. Human pulmonary artery endothelial cells (HPAECs) were cultured to confluence, and then the monolayers were exposed to either control (21% O(2)-5% CO(2)) or hyperoxic (90% O(2)-5% CO(2)) conditions with and without a synthetic glucocorticoid, methylprednisolone (MP). MP reduced hyperoxia-induced ICAM-1 and ICAM-1 mRNA expression in a dose-dependent manner. Neutrophil adhesion to hyperoxia-exposed endothelial cells was also inhibited by MP treatment. In addition, MP attenuated hyperoxia-induced H(2)O(2) production in HPAECs as assessed by flow cytometry. An electrophoretic mobility shift assay demonstrated that hyperoxia activated nuclear factor-kappaB (NF-kappaB) but not activator protein-1 (AP-1) and that MP attenuated hyperoxia-induced NF-kappaB activation dose dependently. With Western immunoblot analysis, IkappaB-alpha expression was decreased by hyperoxia and increased by MP treatment. These results suggest that MP downregulates hyperoxia-induced ICAM-1 expression by inhibiting NF-kappaB activation via increased IkappaB-alpha expression.
Am J Physiol Lung Cell Mol Physiol 2000 Feb
PMID:Effect of steroid on hyperoxia-induced ICAM-1 expression in pulmonary endothelial cells. 1066 7

The aetiology of recurrent miscarriage (at least three consecutive miscarriages) usually remains unsolved. The vascular endothelial growth factor (VEGF) family of proteins, together with their receptors and the Tie (tyrosine kinase with immunoglobulin and epidermal growth factor homology domains) receptors, are crucial for embryonic development. Therefore, we used immunohistochemistry to analyse the expression of VEGF, the VEGF receptors (VEGFR)-1, -2, and -3, and the Tie-1 and Tie-2 receptors in placental and decidual tissue of women with a history of recurrent miscarriage and missed abortion (MA; n = 12) or blighted ovum (BO; n = 6), and from normal early terminated pregnancies (n = 12). Compared with controls, the MA and BO groups showed: (i) diminished placental trophoblastic VEGF immunoreactivity; (ii) weaker VEGFR-1 and -2 immunoreactivity in decidual vascular endothelium; (iii) reduced placental trophoblastic Tie-1 receptor immunoreactivity; and (iv) reduced decidual vascular endothelial Tie-1 and -2 receptor immunoreactivity. The absence of VEGFR-3 immunoreactivity in decidual vascular endothelium was also noted in all study groups. Interestingly, placental villi from the BO group presented blood vessel-like structures negative for von Willebrand factor, but positive for VEGF, VEGFR-1, -2, -3, Tie-1 and Tie-2 receptor. We conclude that the expression of these antigens may be altered in recurrent miscarriages.
Mol Hum Reprod 2000 Mar
PMID:VEGF, its receptors and the tie receptors in recurrent miscarriage. 1069 77

Endothelium from rat aorta expresses sarco/endoplasmic reticulum Ca2+(SERCA) pump gene SERCA3 where as the smooth muscle expresses SERCA2. This has led to the postulate that vascular endothelium expresses SERCA3. To test this postulate, we examined the SERCA2 and SERCA3 mRNA expression in endothelium and smooth muscle dissected from coronary artery, coronary vein, aorta and vena cava of pig. Smooth muscle from all arteries and veins expressed only the SERCA2 mRNA. Endothelium from coronary artery, coronary vein and aorta expressed both SERCA2 and SERCA3 mRNA but the endothelium from vena cava did not express SERCA3 mRNA although it expressed SERCA2. These observations support the postulate that vascular endothelium expresses SERCA3 but the affirmation is equivocal because vena cava endothelium does not express SERCA3.
Mol Cell Biochem 2000 Jan
PMID:SERCA pump isoform expression in endothelium of veins and arteries: every endothelium is not the same. 1072 27

Pregnancy is associated with a significant increase in uterine blood flow which contributes to optimal fetal development. Although neuropeptide Y (NPY) is considered to be an important regulator of uterine blood flow, it is not known whether: (i) products from the vascular endothelium modulate NPY action in the uterine artery; (ii) pregnancy changes the responsiveness of the uterine artery to NPY, or (iii) NPY interacts with noradrenaline and acetylcholine on the uterine artery, with pregnancy regulating this possible interaction. In the present study, NPY induced a concentration-dependent contraction of guinea pig uterine arterial rings both intact and denuded of endothelium. Pregnancy significantly decreased the potency of NPY to contract uterine artery with and without endothelium. In all preparations, addition of N(G)-monomethyl-l-arginine acetate (l-NMMA), indomethacin and diethylcarbamazine did not modify the effect of NPY. In the presence of NPY concentration-response curves for acetylcholine and noradrenaline were significantly shifted to the right and left respectively. This effect of NPY was independent of endothelial condition or pregnancy status. The receptor reserve (K(A)/EC(50)) for acetylcholine was decreased and for noradrenaline was increased in the presence of NPY, although no changes in the dissociation constants of the neurotransmitter-receptor complexes were observed. Thus, this study has shown that: (i) NPY induces contraction of guinea pig uterine arteries acting on receptors localized in smooth muscle; (ii) pregnancy alters the response of guinea pig uterine arteries to NPY in such a way as to promote vasorelaxation, and (iii) NPY modulates the effect of neurotransmitters on guinea pig uterine arteries, but pregnancy is not associated with the changes at the level of NPY-neurotransmitter interaction.
Mol Hum Reprod 2000 Apr
PMID:Pregnancy is associated with altered response to neuropeptide Y in uterine artery. 1072 18

Vasculogenesis and angiogenesis are the mechanisms responsible for the development of the blood vessels. Angiogenesis refers to the formation of capillaries from pre-existing vessels in the embryo and adult organism, while vasculogenesis is the development of new blood vessels from the differentiation of endothelial precursors (angioblasts) in situ. Vascular endothelial growth factor (VEGF) family members are major mediators of vasculogenesis and angiogenesis both during development and in pathological conditions. VEGF has a variety of effects on vascular endothelium, including the ability to promote endothelial cell viability, mitogenesis, chemotaxis, and vascular permeability. It mediates its activity mainly via two tyrosine kinase receptors, VEGFR-1 (flt-1) and VEGFR-2 (flk-1/KDR), although other receptors, such as neuropilin-1 and -2, can also bind VEGF. Another tyrosine kinase receptor, VEGFR-3 (flt-4) binds VEGF-C and VEGF-D and is more important in the development of lymphatic vessels. While the functional effects of VEGF on endothelial cells has been well studied, not as much is known about VEGF signaling. This review summarizes the different pathways known to be involved in VEGF signal transduction and the biological responses triggered by the VEGF signaling cascade.
Int J Mol Med 2000 May
PMID:Signaling pathways induced by vascular endothelial growth factor (review). 1076 46

To determine how histamine regulates endothelial barrier function through an integrative cytoskeletal network, we mathematically modeled the resistance across an endothelial cell-covered electrode as a function of cell-cell, cell-matrix, and transcellular resistances. Based on this approach, histamine initiated a rapid decrease in transendothelial resistance predominantly through decreases in cell-cell resistance in confluent cultured human umbilical vein endothelial cells (HUVECs). Restoration of resistance was characterized by initially increasing cell-matrix resistance, with later increases in cell-cell resistance. Thus histamine disrupts barrier function by specifically disrupting cell-cell adhesion and restores barrier function in part through direct effects on cell-matrix adhesion. To validate the precision of our technique, histamine increased the resistance in subconfluent HUVECs in which there was no cell-cell contact. Exposure of confluent monolayers to an antibody against cadherin-5 caused a predominant decrease in cell-cell resistance, whereas the resistance was unaffected by the antibody to cadherin-5 in subconfluent cells. Furthermore, we observed an increase predominantly in cell-cell resistance in ECV304 cells that were transfected with a plasmid containing a glucocorticoid-inducible promoter controlling expression of E-cadherin. Transmission electron microscopy confirmed tens of nanometer displacements between adjacent cells at a time point in which histamine maximally decreased cell-cell resistance.
Am J Physiol Lung Cell Mol Physiol 2000 May
PMID:Histamine alters endothelial barrier function at cell-cell and cell-matrix sites. 1078 18


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