Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Extensive angiogenesis and invasion of the maternal decidua by trophoblasts are essential for the development and function of the placenta. Vascular endothelial growth factors (VEGF), placenta growth factor (PlGF) and their receptors VEGFR-1/Flt-1, VEGFR-2/KDR and VEGFR-3/Flt4 have important roles in vasculogenesis and angiogenesis. We have studied the localization of these proteins by immunohistochemistry and Western blotting in the placenta and of PlGF in maternal serum, and their association with diabetes, pre-eclampsia, fetal growth restriction (FGR) and fetal alcohol syndrome (FAS). VEGFR-1 and VEGFR-3 were detected mainly in the syncytiotrophoblastic layer whereas VEGFR-2 was detected in the vascular endothelial cells of the placenta. VEGFR-1, but not the other receptors, showed increased expression in placental syncytiotrophoblasts from 50% of patients with severe pre-eclampsia and FGR when compared with normal placentas. PlGF was undetectable in 38 of 44 samples of amniotic fluid of mothers with normal and complicated pregnancies. However, maternal serum PlGF concentrations were significantly lower in pre-eclamptic patients and in those with FGR when compared to diabetic women or healthy controls. These results suggest that low maternal serum PlGF and increased placental expression of its receptor VEGFR-1 are associated with pre-eclampsia and FGR.
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PMID:Expression of vascular endothelial growth factor receptors 1, 2 and 3 in placentas from normal and complicated pregnancies. 1116 Aug 48

Intrauterine growth restriction (IUGR) is a significant cause of infant mortality and morbidity. It is now clear that IUGR infants exhibit higher rates of coronary heart disease, type 2-diabetes, hypertension and stroke as adults. Therefore, fetal growth not only impacts the outcome of the perinatal period, but also impacts adult well-being. The etiologies of IUGR are numerous, but are often associated with abnormalities in placental structure and function. The process of implantation and placentation requires the production of a plethora of growth factors, cell-adhesion molecules, extracellular matrix proteins, hormones and transcription factors. Many of these exhibit altered expression within the placenta of IUGR pregnancies. However, it has been difficult to fully assess their role during the development of placental insufficiency (PI) in the human, underscoring the need for animal models. Using an ovine model of PI-IUGR we have observed changes in the expression of vascular endothelial growth factor, placental growth factor, their common receptors, as well as angiopoietin 2 and its receptor, Tie 2. We found that changes in these growth factors can be associated with both acute and chronic changes in placental vascular structure and function. These studies and others are providing needed insight into the developmental chronology of placental insufficiency.
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PMID:Placental development in normal and compromised pregnancies-- a review. 1197 69

Vascular insufficiency and retinal ischemia precede many proliferative retinopathies and stimulate secretion of various vasoactive growth factors, including vascular endothelial growth factor (VEGF) and placenta growth factor (PlGF). It is unclear, however, how PlGF, which is elevated in proliferative diabetic retinopathy and is a VEGF homolog that binds only to VEGF receptor (VEGFR)-1, promotes pathological angiogenesis. When primary microvascular endothelial cells were grown on collagen gels, PlGF-containing ligands upregulated Bcl-2 expression and stimulated the formation of capillary-like tube networks that were retained for up to 14 days in culture. The inhibition of VEGFR-1 results in a dramatic decrease in the number of capillary connections, indicating that VEGFR-1 ligands promote branching angiogenesis. In contrast, VEGF-induced tube formations and Bcl-2 expression were significantly decreased at the end of this period. Flow cytometry analysis of annexin-V/propidium iodide-stained cells revealed that PlGF and PlGF/VEGF heterodimer inhibited apoptosis in serum-deprived endothelial cells. These two growth factors stimulated a survival signaling pathway phosphatidylinositol 3-kinase (PI3K), as identified by increased Akt phosphorylation and because blocking PI3K signalling by adenovirus-mediated overexpression of wild-type phosphatase and tensin homolog on chromosome 10 (PTEN) disrupted angiogenesis and decreased Bcl-2 expression by PlGF and PlGF/VEGF heterodimer, whereas a dominant-negative PTEN mutant enhanced endothelial sprout formation and Bcl-2 expression. Together, these findings indicate that PlGF-containing ligands contribute to pathological angiogenesis by prolonging cell survival signals and maintaining vascular networks.
Diabetes 2003 Dec
PMID:Activation of vascular endothelial growth factor receptor-1 sustains angiogenesis and Bcl-2 expression via the phosphatidylinositol 3-kinase pathway in endothelial cells. 1463 57

Mechanisms that hinder ischemia-induced neovascularization in diabetes remain poorly understood. We hypothesized that endogenous bone marrow mononuclear cell (BM-MNC) dysfunction may contribute to the abrogated postischemic revascularization reaction associated with diabetes. We first analyzed the effect of diabetes (streptozotocin, 40 mg/kg) on BM-MNC pro-angiogenic potential in a model of surgically induced hindlimb ischemia. In nondiabetic animals, transplantation of BM-MNCs isolated from nondiabetic animals raised the ischemic/nonischemic angiographic score, capillary number, and blood flow recovery by 1.8-, 2.7-, and 2.2-fold, respectively, over that of PBS-injected nondiabetic animals (P < 0.05). Administration of diabetic BM-MNCs also improved the neovascularization reaction in ischemic hindlimbs of nondiabetic mice but to a lesser extent from that observed with nondiabetic BM-MNC transplantation. In diabetic mice, injection of nondiabetic BM-MNCs was still more efficient than that of diabetic BM-MNCs. Such BM-MNC dysfunction was associated with the impairment of diabetic BM-MNC capacity to differentiate into endothelial progenitor cells (EPCs) in vitro and to participate in vascular-like structure formation in a subcutaneous Matrigel plug. Placenta growth factor (PlGF) administration improved by sixfold the number of EPCs differentiated from diabetic BM-MNCs in vitro and enhanced ischemic/nonischemic angiographic score, capillary number and blood flow recovery by 1.9-, 1.5- and 1.6-fold, respectively, over that of untreated diabetic animals (P < 0.01). Endogenous BM-MNC pro-angiogenic potential was affected in diabetes. Therapeutic strategy based on PlGF administration restored such defects and improved postischemic neovascularization in diabetic mice.
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PMID:Impairment in ischemia-induced neovascularization in diabetes: bone marrow mononuclear cell dysfunction and therapeutic potential of placenta growth factor treatment. 1474 52

Placenta growth factor (PlGF) has been implicated in both physiological and pathological angiogenesis; however, little is known about what regulates its expression. In this study, retinal microvascular endothelial cells and pericytes were exposed to varying concentrations of VEGF and glucose and PlGF expression measured by RT-PCR and Western blotting. Both PlGF mRNA and protein were observed in unstimulated microvascular endothelial cells with only weak expression in pericytes. In endothelial cells, VEGF (100 ng/ml) and glucose (15 mM) induced an increase in expression of PlGF at both the mRNA and protein level while no effect was observed for pericytes. The increase in PlGF expression could be totally abolished by blocking VEGFR-2, and in the case of glucose by neutralising VEGF. VEGF-stimulated PlGF expression was largely inhibited by PD 98059, an inhibitor of mitogen-activated protein kinase (MAPK) and partially by GF 109203X, an inhibitor of protein kinase C (PKC), indicating that VEGF up-regulates PlGF expression via the MAPK signalling pathway and partially through PKC. Taken together, our findings suggest that VEGF orchestrates the contribution of PlGF in angiogenesis via more than one intracellular pathway and that hyperglycaemia, as occurs in diabetes, is an important regulator of PlGF expression via VEGF up-regulation.
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PMID:Expression of placenta growth factor is regulated by both VEGF and hyperglycaemia via VEGFR-2. 1550 Dec 43

Reduced microcirculation and diminished expression of growth factors contribute to wound healing impairment in diabetes. Placenta growth factor (PlGF), an angiogenic mediator promoting pathophysiological neovascularization, is expressed during cutaneous wound healing and improves wound closure by enhancing angiogenesis. By using streptozotocin-induced diabetic mice, we here demonstrate that PlGF induction is strongly reduced in diabetic wounds. Diabetic transgenic mice overexpressing PlGF in the skin displayed accelerated wound closure compared with diabetic wild-type littermates. Moreover, diabetic wound treatment with an adenovirus vector expressing the human PlGF gene (AdCMV.PlGF) significantly accelerated the healing process compared with wounds treated with a control vector. The analysis of treated wounds showed that PlGF gene transfer improved granulation tissue formation, maturation, and vascularization, as well as monocytes/macrophages local recruitment. Platelet-derived growth factor, fibroblast growth factor-2, and vascular endothelial growth factor mRNA levels were increased in AdCMV.PlGF-treated wounds, possibly enhancing PlGF-mediated effects. Finally, PlGF treatment stimulated cultured dermal fibroblast migration, pointing to a direct role of PlGF in accelerating granulation tissue maturation. In conclusion, our data indicate that reduced PlGF expression contributes to impaired wound healing in diabetes and that PlGF gene transfer to diabetic wounds exerts therapeutic activity by promoting different aspects of the repair process.
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PMID:Placenta growth factor in diabetic wound healing: altered expression and therapeutic potential. 1700 76

The placenta produces several growth factors, including placenta growth factor (PlGF), which are essential for placenta growth and fetal growth. Diabetic pregnancy induces the abnormal placental growth and fetal development. This study investigated whether diabetes in pregnant rats induces changes in PlGF expression in the placenta. Diabetes was induced by a single intravenous injection of streptozotocin (35 mg/kg body weight) on day 0 of pregnancy, blood and tissue samples were collected on day 20 of pregnancy. In the diabetic group, maternal body weight and fetal weight significantly decreased compared to controls. RT-PCR and Western blot analyses showed that expression of PlGF was significantly decreased in placenta by streptozotocin treatment. Immunohistochemical study showed that the positive signal of PlGF in trophoblast cells was decreased in the diabetic group compared to controls. These findings demonstrate the decline of PlGF in the placenta in diabetic pregnancy.
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PMID:Streptozotocin-induced diabetes decreases placenta growth factor (PlGF) levels in rat placenta. 1791 70

Wound healing is impaired in elderly patients with diabetes mellitus. We hypothesized that age-dependent impairment of cutaneous wound healing in db/db diabetic mice: (a) would correlate with reduced expression of the transcription factor hypoxia-inducible factor 1alpha (HIF-1alpha) as well as its downstream target genes; and (b) could be overcome by HIF-1alpha replacement therapy. Wound closure, angiogenesis, and mRNA expression in excisional skin wounds were analyzed and circulating angiogenic cells (CACs) were quantified in db/db mice that were untreated or received electroporation-facilitated HIF-1alpha gene therapy. HIF-1alpha mRNA levels in wound tissue were significantly reduced in older (4-6 months) as compared to younger (1.5-2 months) db/db mice. Expression of mRNAs encoding the angiogenic cytokines vascular endothelial growth factor (VEGF), angiopoietin 1 (ANGPT1), ANGPT2, platelet-derived growth factor B (PDGF-B), and placental growth factor (PLGF) was also impaired in wounds of older db/db mice. Intradermal injection of plasmid gWIZ-CA5, which encodes a constitutively active form of HIF-1alpha, followed by electroporation, induced increased levels of HIF-1alpha mRNA at the injection site on day 3 and increased levels of VEGF, PLGF, PDGF-B, and ANGPT2 mRNA on day 7. CACs in peripheral blood increased 10-fold in mice treated with gWIZ-CA5. Wound closure was significantly accelerated in db/db mice treated with gWIZ-CA5 as compared to mice treated with empty vector. Thus, HIF-1alpha gene therapy corrects the age-dependent impairment of HIF-1alpha expression, angiogenic cytokine expression, and CACs that contribute to the age-dependent impairment of wound healing in db/db mice.
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PMID:Age-dependent impairment of HIF-1alpha expression in diabetic mice: Correction with electroporation-facilitated gene therapy increases wound healing, angiogenesis, and circulating angiogenic cells. 1850 85

The objective of this study was to investigate the role of vascular endothelial growth factor-A (VEGF-A) and placental growth factor-2 (PlGF-2) in fetal malformations associated with maternal diabetes. Diabetes was induced in female rats. Diabetic and control female rats were made pregnant. On Day 15 of gestation, rats were sacrificed and embryos and their placentas and membranes were dissected out of the uterine horns. Following morphological examination, embryos and their placentas and membranes were homogenized and used for assayed of VEGF-A and PlGF-2 levels. Embryos of diabetic mothers, exhibited significantly (P < 0.05) shorter crown-to-rump lengths, smaller weights, and heavier placental weights. Experimentally induced maternal diabetes was accompanied by decreased VEGF-A in embryos and associated structures. The levels of PlGF-2 in non-malformed embryos of diabetic gestation and their placentas were significantly (P < 0.05) lower than the average of controls. These results might indicate defective vascularization with a consequent morphological or anatomical anomalies or more subtle biochemical or metabolic changes. In diabetic mothers, a statistically significant (P < 0.05) decrease was noted in the level of VEGF-A in plasma of diabetic rats with a small non-significant decrease in PlGF-2. Like many other diabetic complications, diabetes-induced embryopathies might have vascular origin and correcting the disturbances in these angiogenic factors might help decrease the incidence of malformation in diabetic gestation.
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PMID:The levels of vascular endothelial growth factor-A and placental growth factor-2 in embryopathy associated with experimental diabetic gestation. 1904 27

To determine the effect of diabetes on reproductive performance, two kinds of diabetes mice, i.e., KK/TaJcl mice with Type-II diabetes and Streptozotocin-induced diabetes mice with Type-I diabetes, were used in this study. Particular attention was paid to uterine natural killer (uNK) cells and placental growth factor (PlGF). The number of fetuses, the fetal and placental weights in both diabetes mice were significantly decreased when compared to controls. Surprisingly, uNK cells in both diabetes mice persisted in the metrial gland even at the term of pregnancy. Although PlGF expression in both diabetes mice was significantly decreased, PlGF protein did not change. These results show that diabetes condition affects reproductive performance, particularly uNK cell behavior, but not PlGF production.
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PMID:Reproductive performance in diabetes mice with a special reference to uterine natural killer cells and placental growth factor. 1942 Aug 61


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