Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder because of mutations in the genes coding for endoglin (HHT1) or ALK-1 (HHT2). The disease is associated with haploinsufficiency and a murine model was obtained by engineering mice that express a single Endoglin allele. Of a total of 171 mice that were observed for 1 year, 50 developed clinical signs of HHT. Disease prevalence was high in 129/Ola strain (72%), intermediate in the intercrosses (36%), and low in C57BL/6 backcrosses (7%). Most mice first presented with an ear telangiectasia and/or recurrent external hemorrhage. One-third of mice with HHT showed severe vascular abnormalities such as dilated vessels, hemorrhages, liver and lung congestion, and/or brain and heart ischemia. Disease sequelae included stroke, hydrocephalus, fatal hemorrhage, and congestive heart failure. Thus the murine model reproduces the multiorgan manifestations of the human disease. Levels of circulating latent transforming growth factor (TGF)-beta1 were significantly lower in the 129/Ola than in the C57BL/6 strain. Intercrosses and 129/Ola mice expressing reduced endoglin also showed lower plasma TGF-beta1 levels than control. These data suggest that modifier genes involved in the regulation of TGF-beta1 expression act in combination with a single functional copy of endoglin in the development of HHT.
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PMID:Potential role of modifier genes influencing transforming growth factor-beta1 levels in the development of vascular defects in endoglin heterozygous mice with hereditary hemorrhagic telangiectasia. 1139 79

Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu disease, is an hereditary disorder that results in fibrovascular dysplasia with the development of telangiectasias and arteriovenous malformations. It predominantly involves the skin, mucous membranes, viscera, lungs, and brain. Hereditary hemorrhagic telangiectasia shows great genetic heterogeneity, and its phenotypes have been classified based on the recently identified mutated genes: endoglin (HHT-1) and activin-like kinase receptor-1 (HHT-2). Other families with phenotypic HHT do not bear these mutations; therefore, other genes are probably involved as well. Liver involvement is reported in up to 30% of persons affected by HHT. Large arteriovenous malformations in the liver can lead to significant complications, including high-output congestive heart failure, portal hypertension, hepatic encephalopathy, biliary ischemia, and liver failure. Embolization of large arteriovenous malformations in the liver remains controversial; however, liver transplantation can successfully eradicate these complications.
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PMID:Liver disease in hereditary hemorrhagic telangiectasia. 1254

Vascular targeting agents (VTAs) for the treatment of cancer are designed to cause a rapid and selective shutdown of the blood vessels of tumors. Unlike antiangiogenic drugs that inhibit the formation of new vessels, VTAs occlude the pre-existing blood vessels of tumors to cause tumor cell death from ischemia and extensive hemorrhagic necrosis. Tumor selectivity is conferred by differences in the pathophysiology of tumor versus normal tissue vessels (e.g., increased proliferation and fragility, and up-regulated proteins). VTAs can kill indirectly the tumor cells that are resistant to conventional antiproliferative cancer therapies, i.e., cells in areas distant from blood vessels where drug penetration is poor, and hypoxia can lead to radiation and drug resistance. VTAs are expected to show the greatest therapeutic benefit as part of combined modality regimens. Preclinical studies have shown VTA-induced enhancement of the effects of conventional chemotherapeutic agents, radiation, hyperthermia, radioimmunotherapy, and antiangiogenic agents. There are broadly two types of VTAs, small molecules and ligand-based, which are grouped together, because they both cause acute vascular shutdown in tumors leading to massive necrosis. The small molecules include the microtubulin destabilizing drugs, combretastatin A-4 disodium phosphate, ZD6126, AVE8062, and Oxi 4503, and the flavonoid, DMXAA. Ligand-based VTAs use antibodies, peptides, or growth factors that bind selectively to tumor versus normal vessels to target tumors with agents that occlude blood vessels. The ligand-based VTAs include fusion proteins (e.g., vascular endothelial growth factor linked to the plant toxin gelonin), immunotoxins (e.g., monoclonal antibodies to endoglin conjugated to ricin A), antibodies linked to cytokines, liposomally encapsulated drugs, and gene therapy approaches. Combretastatin A-4 disodium phosphate, ZD6126, AVE8062, and DMXAA are undergoing clinical evaluation. Phase I monotherapy studies have shown that the agents are tolerated with some demonstration of single agent efficacy. Because efficacy is expected when the agents are used with conventional chemotherapeutic drugs or radiation, the results of Phase II combination studies are eagerly awaited.
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PMID:Vascular targeting agents as cancer therapeutics. 1476 60

Hereditary Hemorrhagic telangiectasia is an autosomal dominant vascular disorder with high penetrance and variable expressivity. Most cases are caused by mutations in the endoglin gene on chromosome 9 (HHT type 1) or the activin receptor-like kinase 1 gene on chromosome 12 (HHT type 2). HHT is characterized by mucocutaneous telangiectases and visceral arteriovenous malformations (AVMs). Neurological complications occur in 8 to 10% of the patients. Brain ischemia or abscess are often associated with pulmonary arteriovenous fistula. Cerebral or spinal arteriovenous malformations are frequent but have a lower risk of haemorrhage than sporadic AVMs and routine screening should not be practiced in adult patients. Routine screening should be discussed for children with a familial history of cerebral haemorrhage and/or HHT type 1.
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PMID:[Neuroimaging of hereditary hemorrhagic telangiectasia]. 1613 98

Hypertensive disorders of pregnancy continue to be a significant source of maternal and fetal morbidity and mortality, and recent evidence suggests that the incidence of preeclampsia (PE) is increasing. Recent epidemiological studies indicate that the effects of PE may persist long after pregnancy, in both the mother and the offspring, as increased incidence of cardiovascular disease. The last decade has produced new insights into the pathogenesis of PE. The initiating event in PE appears to be impaired placental perfusion and subsequent placental ischemia, which results in the elaboration of numerous factors. Factors such as soluble fms-like tyrosine kinase-1, soluble endoglin and the angiotensin II type-1 receptor autoantibodies contribute to maternal endothelial and cardiovascular dysfunction, marked by increased reactive oxygen species and decreased bioavailable VEGF, nitric oxide and prostacyclin. However, the importance of the various endothelial and humoral factors that mediate these changes during PE remain to be elucidated.
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PMID:Placental ischemia and cardiovascular dysfunction in preeclampsia and beyond: making the connections. 1901 90

Recent clinical studies indicate that an excess of angiostatic factors, such as soluble endoglin (sEng), is related to the occurrence of preeclampsia. Although recent clinical studies report that sEng is increased in preeclamptic women, the mechanisms underlying its overexpression remain unclear. Evidence suggests that hypoxia and induction of heme oxygenase-1 have opposing effects on sEng expression, the former stimulatory and the latter inhibitory. Hence, we hypothesized that placental ischemia because of reduced uterine perfusion pressure (RUPP) in the pregnant rat would increase sEng expression and decrease heme oxygenase-1. Mean arterial pressure was obtained via arterial catheter, and serum and placental proteins were measured by Western blot. Mean arterial pressure was increased (132+/-3 mm Hg versus 102+/-2 mm Hg; P<0.001), and fetal (2.35+/-0.05 g versus 1.76+/-0.08 g; P<0.001) and placental weight were decreased (0.47+/-0.04 g versus 0.58+/-0.03 g; P<0.01) in the RUPP compared with normal pregnant controls. Serum sEng (0.10+/-0.02 arbitrary pixel units [apu] versus 0.05+/-0.01 apu; P<0.05) and placental endoglin (4.7+/-2.3 apu versus 1.45+/-0.42 apu; P<0.05) were increased along with placental hypoxia inducible factor-1 alpha (1.42+/-0.25 apu versus 0.68+/-0.09 apu; P<0.05) expression in the RUPP versus the normal pregnant dams. Placental HO-1 (1.4+/-0.3 apu versus 2.5+/-0.1 apu; P<0.05) expression decreased in the RUPP compared with normal pregnant dams. The present findings support our hypothesis that placental ischemia because of RUPP increases the expression of sEng and shifts the balance of angiogenic factors in the maternal circulation toward an angiostatic state. The present study provides further evidence that placental ischemia is a strong in vivo stimulus of angiostatic factors during pregnancy.
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PMID:Hypertension produced by placental ischemia in pregnant rats is associated with increased soluble endoglin expression. 1907 97

Although hypertensive disorders of pregnancy, such as preeclampsia, continue to be a significant source of maternal and fetal morbidity and mortality, there is emerging evidence that effects of the preeclamptic syndrome persist into later life. In contrast to recent studies that have reported that formerly preeclamptic women are at increased risk for cardiovascular disease, it appears that preeclampsia may be associated with a decreased risk of breast cancer. Recent investigations have provided exciting new insights into potential mechanisms underlying the pathogenesis of preeclampsia and some of these findings may bear relevance to the anticancer effects reported in the epidemiological literature. Placental ischemia is regarded to be a primary factor in preeclampsia and the ischemic placenta produces a variety of factors that generate profound effects on endothelial cell function and the cardiovascular system during pregnancy. Moreover, several of these factors are reportedly elevated many years after preeclamptic pregnancies. This group of molecules includes factors such as soluble fms-like tyrosine kinase-1 (sFlt-1), soluble endoglin/CD105 (sEng) and various cytokines. Many of these factors have been strongly associated with cancer incidence and, hence, could contribute to the modification of cancer risk observed in these women. Therefore, identifying potential connections between placental dysfunction and future cancer risk is an important endeavor towards realizing novel therapeutic regimens for cancer patients.
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PMID:Placental ischemia and breast cancer risk after preeclampsia: tying the knot. 1944 83

It is hypothesized that in some women an excessively high intra-abdominal pressure (IAP) compresses the inferior vena cava, uterine veins, portal vein, hepatic veins, splenic vein and renal veins which lead to a decreased flow in these vascular beds, producing lower extremity edema, fetal-placental ischemia, a glomerulopathy with proteinuria and hypertension, hepatic ischemia and thrombocytopenia, increased uric acid, and hemolysis/elevated liver enzymes/low platelet known as the HELLP syndrome. There can be variability in the expression of these components. Placental-fetal ischemia could lead to expression of soluble fms-like tyrosine kinase1 (sFLT) and endoglin which have been shown to cause additional diffuse endovascular damage. A further increase in IAP pushes the diaphragm cephalad, increasing intrathoracic pressure leading to upper extremity edema, decreased internal jugular venous flow, cerebral vascular engorgement, raised intracranial pressure, and if unresolved, seizures. Placental/fetal ischemia and hepatic ischemic necrosis may lead to diffuse inflammation and a septic inflammatory response syndrome (SIRS) which may become a vicious cycle, perpetuating the ischemia. It is further hypothesized that application of an externally applied negative abdominal pressure device will lower IAP and possibly reverse the pathophysiology of preeclampsia. As the abnormal placental proteins develop weeks before clinical preeclampsia, early application of external negative abdominal pressure may prevent development of the syndrome.
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PMID:Hypothesis: preeclampsia is a venous disease secondary to an increased intra-abdominal pressure. 2186 36

Hypertensive disorders of pregnancy such as preeclampsia present an increasing source of concern during gestation and accumulating evidence suggests there are long-term effects on the subsequent health of the mother and child. While formerly preeclamptic women have increased risk for later cardiovascular disease, they appear to have decreased risk of some cancers. Recent investigations have revealed exciting insights into potential mechanisms underlying the pathogenesis of preeclampsia and some of these findings may bear relevance to the attenuated cancer risk reported in the literature. Placental ischemia, regarded as a primary initiating factor in preeclampsia, results in elevated levels of factors such as soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin/CD105 (sEng) that generate profound effects on the vascular endothelium and cardiovascular function. Further, these factors may also influence development of susceptible organs such as the mammary. Moreover, recent evidence suggests these molecules may be regulated by factors derived from cigarette smoke. Taken together, elucidating mechanisms linking placental ischemia, endothelial function and subsequent cancer risk is an important step towards identifying novel therapies for cancer.
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PMID:The opposing roles of anti-angiogenic factors in cancer and preeclampsia. 2265 76

A disturbed balance between angiogenic and antiangiogenic growth factors is a highly accepted mechanism in the pathogenesis of pregnancy-induced hypertension and proteinuria, which is clinically known as preeclampsia (PE). We investigated the effect of magnesium sulfate (MgSO4) therapy on vascular endothelial growth factor (VEGF), placental growth factor (PlGF), nitric oxide (NO) metabolites, soluble fm-like tyrosine kinase-1 (sFlt-1) and endoglin levels in PE rats and the effect of this treatment on the feto-maternal outcome. The PE group showed hypertension, proteinuria and decreased number and weight of live pups relative to the control group. This result was associated with increased sFlt-1, VEGF receptor-2 (VEGFR-2), VEGFR-3 and endoglin levels but decreased NO metabolites. MgSO4 therapy ameliorated systolic hypertension and proteinuria and decreased sFlt-1, VEGFR-2, VEGFR-3 and endoglin levels but increased NO metabolites in the treated group. Physiological and biochemical changes and improved pup weight and viability were observed in the treated group. The vasodilator action of MgSO4 and increased NO production are expected to increase placental blood flow and help fetal nutrition and development. Relief of placental ischemia decreases the production of antiangiogenic growth factors and restores the bioavailability of angiogenic factors (PlGF and VEGF). These changes resulted in better fetal outcome and an improved clinical picture of PE. These findings are promising and encourage further study of the mechanism of action of MgSO(4) to support its widespread use in the prevention and management of the etiopathological changes underlying the vast majority of the manifestations and complications of PE.
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PMID:Magnesium sulfate therapy of preeclampsia: an old tool with new mechanism of action and prospect in management and prophylaxis. 2276 74


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