Neutralization of circulating vascular endothelial growth factor (VEGF) by anti-VEGF antibodies and soluble VEGF receptor 1 (sFlt-1) induces proteinuria.
ABSTRACT There are about 2.5 million glomeruli in the kidneys each consisting of a barrel of glomerular basement membrane surrounded by glomerular endothelial cells on the inside and glomerular epithelial cells with established foot processes (podocytes) on the outside. Defects in this filtration apparatus lead to glomerular vascular leak or proteinuria. The role of vascular endothelial growth factor (VEGF) in the regulation of glomerular vascular permeability is still unclear. Recent studies indicate that patients receiving anti-VEGF antibody therapy may have an increased incidence of proteinuria. In a different setting, pregnancies complicated by preeclampsia are associated with elevated soluble VEGF receptor 1 protein (sFlt-1), endothelial cell dysfunction and proteinuria. These studies suggest that neutralization of physiologic levels of VEGF, a key endothelial survival factor, may lead to proteinuria. In the present study, we evaluated the potential of anti-VEGF neutralizing antibodies and sFlt-1 in the induction of proteinuria. Our studies demonstrate that anti-VEGF antibodies and sFlt-1 cause rapid glomerular endothelial cell detachment and hypertrophy, in association with down-regulation of nephrin, a key epithelial protein in the glomerular filtration apparatus. These studies suggest that down-regulation or neutralization of circulating VEGF may play an important role in the induction of proteinuria in various kidney diseases, some forms of cancer therapy and also in women with preeclampsia.
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ABSTRACT: Preeclampsia is a vascular disorder of pregnancy where anti-angiogenic factors, systemic inflammation and oxidative stress predominate, but none can claim to cause preeclampsia. This review provides an alternative to the ‘two stage model’ of preeclampsia in which abnormal spiral arteries modification leads to placental hypoxia, oxidative stress and aberrant maternal systemic inflammation. Very high maternal soluble fms-like tyrosine kinase-1 (sFlt-1) and very low placenta growth factor (PlGF) are unique to preeclampsia; however, abnormal spiral arteries and excessive inflammation are also prevalent in other placental disorders. Metaphorically speaking pregnancy can be viewed as a car with an accelerator and brakes, where inflammation, oxidative stress and an imbalance in the angiogenic milieu act as ‘accelerator’. The ‘braking system’ includes the protective pathways of heme oxygenase-1 (Hmox1 also referred as HO-1) and cystathionase (Cth, also know as cystathionine γ-lyase, CSE), which generate carbon monoxide (CO) and hydrogen sulfide (H2S) respectively. The failure in these pathways (brakes) results in the pregnancy going out of control and the system crashing. Put simply, preeclampsia is an accelerator-brake defect disorder. CO and H2S hold great promise due to their unique ability to suppress the anti-angiogenic factors sFlt-1 and soluble Endoglin as well as to promote PlGF and endothelial nitric oxide sysnthase activity. The key to finding a cure lies in the identification of cheap, safe and effective drugs that induce the braking system to keep the pregnancy vehicle on track past the finishing line.British Journal of Pharmacology 10/2014; · 5.07 Impact Factor
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ABSTRACT: The vascular endothelium operates in a highly polarized environment, but to date there has been little exploration of apicobasal polarization of its signaling. We show that VEGF-A, histamine, IGFBP3, and LPA trigger unequal endothelial responses when acting from the circulation or the parenchymal side at blood-neural barriers. For VEGF-A, highly polarized receptor distribution contributed to distinct signaling patterns: VEGFR2, which was found to be predominantly abluminal, mediated increased permeability via p38; in contrast, luminal VEGFR1 led to Akt activation and facilitated cytoprotection. Importantly, such differential apicobasal signaling and VEGFR distribution were found in the microvasculature of brain and retina but not lung, indicating that endothelial cells at blood-neural barriers possess specialized signaling compartments that assign different functions depending on whether an agonist is tissue or blood borne.Developmental cell. 08/2014;
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ABSTRACT: The onset of pregnancy implies the appearance of a new organ, the placenta. One main function of the placenta is to supply oxygen to the fetus via hemoproteins. In this review, we highlight the importance of the enzyme heme oxygenase-1 (HO-1) for pregnancy to be established and maintained. HO-1 expression is pivotal to promote placental function and fetal development, thus determining the success of pregnancy. The deletion of the gene Hmox1 in mice leads to inadequate remodeling of spiral arteries and suboptimal placentation followed by intrauterine growth restriction (IUGR) and fetal lethality. A partial Hmox1 deletion leads to IUGR as well, with heterozygote and wild-type fetuses being born, but Hmox1-/- significantly below the expected Mendelian rate. This strong phenotype is associated with diminished number of pregnancy-protective uterine natural killer (uNK) cells. Pregnant heterozygote females develop gestational hypertension. The protective HO-1 effects on placentation and fetal growth can be mimicked by the exogenous administration of carbon monoxide (CO), a product of heme catalyzed by HO-1. CO application promotes the in situ proliferation of uNK cells, restores placentation and fetal growth, while normalizing blood pressure. Similarly, HO-1 inhibition provokes hypertension in pregnant rats. The HO-1/CO axis plays a pivotal role in sustaining pregnancy and aids in the understanding of the biology of pregnancy and reveals a promising therapeutic application in the treatment of pregnancy complications.Frontiers in Pharmacology 12/2014; 5.