scholarly journals AMP kinase activation improves angiogenesis in pulmonary artery endothelial cells with in utero pulmonary hypertension

2013 ◽  
Vol 304 (1) ◽  
pp. L29-L42 ◽  
Author(s):  
Ru-Jeng Teng ◽  
Jianhai Du ◽  
Adeleye J. Afolayan ◽  
Annie Eis ◽  
Yang Shi ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Hypertension ◽  
Growth Factor ◽  
Pulmonary Artery ◽  
In Utero ◽  
Kinase Activation ◽  
Compound C ◽  
Protein Phosphatase 2 ◽  
Amp Activated Protein Kinase ◽  
Endothelial Growth Factor

Pulmonary artery endothelial cells (PAEC) isolated from fetal lambs with in utero pulmonary hypertension (IPH) have phenotypical changes that lead to increased reactive oxygen species (ROS) formation and impaired angiogenesis. AMP-activated protein kinase (AMPK) is known to be activated by ROS, which is expected to help angiogenesis in IPH-PAEC. The objectives of this study were to investigate AMPK responses in IPH and its role in angiogenesis. We observed that, compared with control PAEC, IPH-PAEC have decreased phosphorylation of AMPKα catalytic subunit and AMPK downstream enzymes, indicating a decrease in AMPK activity. In addition, the expression of AMPK kinases is decreased, and protein phosphatase 2 is increased in IPH-PAEC, potentially contributing to the decreased AMPK activation. Metformin, an AMPK activator, improved IPH-PAEC angiogenesis while increasing endothelial NO synthase (eNOS) serine1179 phosphorylation and decreasing the eNOS-caveolin-1 association. Metformin also increased MnSOD activity and the expression of both eNOS and MnSOD. The increase in angiogenesis by Metformin is abolished by pretreatment with AMPK inhibitor, Compound C. Expression of vascular endothelial growth factor (VEGF) and platelet-derived growth factor β (PDGFβ) are decreased in IPH-PAEC compared with control PAEC and were not altered by Metformin. These data indicate that Metformin improves angiogenesis through mechanisms independent of these angiogenic factors. In conclusion, activation of AMPK restores angiogenesis and increases the bioavailability of nitric oxide in IPH. Whether Metformin is beneficial in the management of pulmonary hypertension requires further investigation.

scholarly journals Mammalian Sprouty-1 and -2 Are Membrane-Anchored Phosphoprotein Inhibitors of Growth Factor Signaling in Endothelial Cells

2001 ◽  
Vol 152 (5) ◽  
pp. 1087-1098 ◽  
Author(s):  
Maria-Antonietta Impagnatiello ◽  
Stefan Weitzer ◽  
Grainne Gannon ◽  
Amelia Compagni ◽  
Matt Cotten ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Map Kinase ◽  
Tyrosine Kinases ◽  
Functional Characterization ◽  
Leading Edge ◽  
Growth Factor Signaling ◽  
Kinase Activation ◽  
Rtk Signaling ◽  
Endothelial Growth Factor

Growth factor–induced signaling by receptor tyrosine kinases (RTKs) plays a central role in embryonic development and in pathogenesis and, hence, is tightly controlled by several regulatory proteins. Recently, Sprouty, an inhibitor of Drosophila development-associated RTK signaling, has been discovered. Subsequently, four mammalian Sprouty homologues (Spry-1–4) have been identified. Here, we report the functional characterization of two of them, Spry-1 and -2, in endothelial cells. Overexpressed Spry-1 and -2 inhibit fibroblast growth factor– and vascular endothelial growth factor–induced proliferation and differentiation by repressing pathways leading to p42/44 mitogen-activating protein (MAP) kinase activation. In contrast, although epidermal growth factor–induced proliferation of endothelial cells was also inhibited by Spry-1 and -2, activation of p42/44 MAP kinase was not affected. Biochemical and immunofluorescence analysis of endogenous and overexpressed Spry-1 and -2 reveal that both Spry-1 and -2 are anchored to membranes by palmitoylation and associate with caveolin-1 in perinuclear and vesicular structures. They are phosphorylated on serine residues and, upon growth factor stimulation, a subset is recruited to the leading edge of the plasma membrane. The data indicate that mammalian Spry-1 and -2 are membrane-anchored proteins that negatively regulate angiogenesis-associated RTK signaling, possibly in a RTK-specific fashion.

Plasma vascular endothelial growth factor A and placental growth factor: novel biomarkers of pulmonary hypertension in congenital diaphragmatic hernia

2015 ◽  
Vol 308 (4) ◽  
pp. L378-L383 ◽  
Author(s):  
Neil Patel ◽  
Florian Moenkemeyer ◽  
Susie Germano ◽  
Michael M. H. Cheung
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Pulmonary Hypertension ◽  
Growth Factor ◽  
Pulmonary Artery ◽  
Cardiac Function ◽  
Congenital Diaphragmatic Hernia ◽  
Placental Growth Factor ◽  
Vascular Endothelial ◽  
Endothelial Growth Factor ◽  
Pulmonary Vascular Development

Pulmonary hypertension (PH) due to abnormal pulmonary vascular development is an important determinant of illness severity in congenital diaphragmatic hernia (CDH). Vascular endothelial growth factor A (VEGFA) and placental growth factor (PLGF) may be important mediators of pulmonary vascular development in health and disease. This prospective study investigated the relationship between plasma VEGFA and PLGF and measures of pulmonary artery pressure, oxygenation, and cardiac function in CDH. A cohort of 10 infants with CDH consecutively admitted to a surgical neonatal intensive care unit (NICU) was recruited. Eighty serial plasma samples were obtained and analyzed by multiplex immunoassay to quantify VEGFA and PLGF. Concurrent assessment of pulmonary artery pressure (PAP) and cardiac function were made by echocardiography. Plasma VEGFA was higher and PLGF was lower in CDH compared with existing normative data. Combined plasma VEGFA:PLGF ratio correlated positively with measures of PAP, diastolic ventricular dysfunction, and oxygenation index. Nonsurvivors had higher VEGFA:PLGF ratio than survivors at days 3–4 of life and in the second week of life. These findings suggest that increased plasma VEGFA and reduced PLGF correlate with clinical severity of pulmonary vascular disease and may be associated with adverse outcome in CDH. This potential role for combined plasma VEGFA and PLGF in CDH as disease biomarkers, pathogenic mediators, and therapeutic targets merits further investigation.

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