Early Disruption of VEGF Receptor Signaling and the Risk for Adult Emphysema.
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ABSTRACT:
SUBMITTER: Le Cras TD
PROVIDER: S-EPMC7047451 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Emphysema is a progressive and fatal lung disease with no cure that is characterized by thinning, enlargement, and destruction of alveoli, leading to impaired gas exchange. Disease progression is due in part to dysregulation of VEGF (vascular endothelial growth factor) signaling in the lungs and increased lung-cell apoptosis. Here we asked whether PR1P (Prominin-1-derived peptide), a novel short peptide we designed that increases VEGF binding to endothelial cells, could be used to improve outcome in in vitro and in vivo models of emphysema. We used computer simulation and in vitro and in vivo studies to show that PR1P upregulated endogenous VEGF receptor-2 signaling by binding VEGF and preventing its proteolytic degradation. In so doing, PR1P mitigated toxin-induced lung-cell apoptosis, including from cigarette-smoke extract in vitro and from LPS in vivo in mice. Remarkably, inhaled PR1P led to significantly increased VEGF concentrations in murine lungs within 30 minutes that remained greater than twofold above that of control animals 24 hours later. Finally, inhaled PR1P reduced acute lung injury in 4- and 21-day elastase-induced murine emphysema models. Taken together, these results highlight the potential of PR1P as a novel therapeutic agent for the treatment of emphysema or other lung diseases characterized by VEGF signaling dysregulation.
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Project description:Vascular endothelial growth factors (VEGF) and their receptors play a central role in the development of cardiovascular system and in vasculature-related processes in the adult organism. Given the critical role of this signaling cascade, intricate control systems have evolved to regulate its function. A new layer of added complexity has been the demonstration of the importance of endocytosis and intracellular trafficking of VEGF receptors in the regulation of VEGF signaling. In this review, we consider an evolving link between VEGF receptor endocytosis, trafficking, and signaling and their biological function.
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Project description:Numerous studies have suggested a link between fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) signaling pathways; however the nature of this link has not been established. To evaluate this relationship we investigated VEGF signaling in endothelial cells with disrupted FGF signaling in vitro and in vivo. We find that endothelial cells lacking FGF signaling become unresponsive to VEGF due to down regulation of VEGFR2 expression caused by reduced Vegfr2 enhancer activation, which is in turn caused by reduced activation of Ets family transcription factors. In vivo this manifests in the loss of vascular integrity and morphogenesis. Thus, basal FGF stimulation of the endothelium is required for maintenance of VEGFR2 expression and the ability to respond to VEGF stimulation and accounts for the hierarchic control of vascular formation by FGFs and VEGF. Primary mouse lung endothelial cells were transduced with either Adeno-Null (empty) or Adeno- dominant negative FGF receptor 1 and harvested 24 hours after transduction. Total RNA was extracted and subjected to the analysis using SuperArray GEArray Q Series Mouse Angiogenesis Gene Array. Comparisons were made between treatments.
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Project description:The Developmental Origins of Health and Disease (DOHaD) Theory proposes that the environment encountered during fetal life and infancy permanently shapes tissue physiology and homeostasis such that damage resulting from maternal stress, poor nutrition or exposure to environmental agents may be at the heart of adult onset disease. Interference with endogenous developmental functions of the aryl hydrocarbon receptor (AHR), either by gene ablation or by exposure in utero to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a potent AHR ligand, causes structural, molecular and functional cardiac abnormalities and altered heart physiology in mouse embryos. To test if embryonic effects progress into an adult phenotype, we investigated whether Ahr ablation or TCDD exposure in utero resulted in cardiac abnormalities in adult mice long after removal of the agent. Ten-months old adult Ahr-/- and in utero TCDD-exposed Ahr+/+ mice showed sexually dimorphic abnormal cardiovascular phenotypes characterized by echocardiographic findings of hypertrophy, ventricular dilation and increased heart weight, resting heart rate and systolic and mean blood pressure, and decreased exercise tolerance. Underlying these effects, genes in signaling networks related to cardiac hypertrophy and mitochondrial function were differentially expressed. Cardiac dysfunction in mouse embryos resulting from AHR signaling disruption seems to progress into abnormal cardiac structure and function that predispose adults to cardiac disease, but while embryonic dysfunction is equally robust in males and females, the adult abnormalities are more prevalent in females, with the highest severity in Ahr-/- females. The findings reported here underscore the conclusion that AHR signaling in the developing heart is one potential target of environmental factors associated with cardiovascular disease.
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Project description:Numerous studies have suggested a link between fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) signaling pathways; however the nature of this link has not been established. To evaluate this relationship we investigated VEGF signaling in endothelial cells with disrupted FGF signaling in vitro and in vivo. We find that endothelial cells lacking FGF signaling become unresponsive to VEGF due to down regulation of VEGFR2 expression caused by reduced Vegfr2 enhancer activation, which is in turn caused by reduced activation of Ets family transcription factors. In vivo this manifests in the loss of vascular integrity and morphogenesis. Thus, basal FGF stimulation of the endothelium is required for maintenance of VEGFR2 expression and the ability to respond to VEGF stimulation and accounts for the hierarchic control of vascular formation by FGFs and VEGF.
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Project description:To investigate whether fetal endothelial cell proliferation and migration are modulated by the A2A adenosine receptor (A2AAR), nitric oxide (NO) and the vascular endothelial growth factor (VEGF) signaling pathway, we isolated human umbilical vein endothelial cells from normal pregnancy (n = 23), preterm delivery (n = 4), and late-onset (LOPE, n = 10) and early-onset preeclampsia (EOPE, n = 8). We used the non-selective adenosine receptor agonist (NECA) and the selective agonist (CGS-21680) and/or selective antagonist (ZM-241385) for A2AAR. Also, the nitric oxide synthase (NOS) inhibitor, L-NAME, was used in co-incubation with CGS-21680. Compared to normal pregnancy, EOPE exhibited low cell proliferation and migration associated with reduced expressions of A2AAR and VEGF and NO synthesis (i.e., total and phosphorylated serine(1177) endothelial NOS and nitrite formation). In contrast, LOPE exhibited the opposite behavior in all these markers compared to normal pregnancy or EOPE. Cell proliferation and migration were increased by CGS-21680 (or NECA) in all analyzed groups (EOPE>LOPE>normal pregnancy) compared to their respective basal conditions, an effect that was associated with high NO and VEGF synthesis and blocked by ZM-241385 with significantly different IC50 for each group (EOPE>LOPE>normal pregnancy). The differences seem independent of gestational age. L-NAME blocked the CGS-21680-mediated cell proliferation and migration in normal pregnancy and LOPE (IC50 = 36.2 ± 2.5 and 8.6 ± 2.2 nM, respectively) as well as the VEGF expression in normal pregnancy. Therefore, the A2AAR/NO/VEGF signaling pathway exhibits a pro-angiogenic effect in normal pregnancies and LOPE, whereas impairment in this pathway seems related to the reduced angiogenic capacity of the fetal endothelium in EOPE.
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Project description:Phosphorylation of serines, threonines, and tyrosines is a central event in signal transduction cascades in eukaryotic cells. The phosphorylation state of any particular protein reflects a balance of activity between kinases and phosphatases. Kinase biology has been exhaustively studied and is reasonably well understood, however, much less is known about phosphatases. A large body of evidence now shows that protein phosphatases do not behave as indiscriminate signal terminators, but can function both as negative or positive regulators of specific signaling pathways. Genetic models have also shown that different protein phosphatases play precise biological roles in health and disease. Finally, genome sequencing has unveiled the existence of many protein phosphatases and associated regulatory subunits comparable in number to kinases. A wide variety of roles for protein phosphatase roles have been recently described in the context of cancer, diabetes, hereditary disorders and other diseases. In particular, there have been several recent advances in our understanding of phosphatases involved in regulation of vascular endothelial growth factor receptor 2 (VEGFR2) signaling. The receptor is the principal signaling molecule mediating a wide spectrum of VEGF signal and, thus, is of paramount significance in a wide variety of diseases ranging from cancer to cardiovascular to ophthalmic. This review focuses on the current knowledge about protein phosphatases' regulation of VEGFR2 signaling and how these enzymes can modulate its biological effects.
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Project description:Very little is known about the influence of early life exposures on adult cancer risk. The purpose of this narrative review was to summarize the epidemiologic evidence relating early life tobacco use, obesity, diet, and physical activity to adult cancer risk; describe relevant theoretical frameworks and methodological strategies for studying early life exposures; and discuss policies and research initiatives focused on early life. Our findings suggest that in utero exposures may indirectly influence cancer risk by modifying biological pathways associated with carcinogenesis; however, more research is needed to firmly establish these associations. Initiation of exposures during childhood and adolescence may impact cancer risk by increasing duration and lifetime exposure to carcinogens and/or by acting during critical developmental periods. To expand the evidence base, we encourage the use of life course frameworks, causal inference methods such as Mendelian randomization, and statistical approaches such as group-based trajectory modeling in future studies. Further, we emphasize the need for objective exposure biomarkers and valid surrogate endpoints to reduce misclassification. With the exception of tobacco use, there is insufficient evidence to support the development of new cancer prevention policies; however, we highlight existing policies that may reduce the burden of these modifiable risk factors in early life.
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