The neutrophil elastase‐upregulated placenta growth factor promotes the pathogenesis and progression of periodontal disease

Abstract Pulmonary hypertension (PHT) develops in sickle cell disease (SCD) and is associated with high mortality. We previously showed that erythroid cells produce placenta growth factor (PlGF), which activates monocytes to induce proinflammatory cytochemokines, contributing to the baseline inflammation and severity in SCD. In this study, we observed that PlGF increased expression of endothelin-1 (ET-1) and endothelin-B receptor (ET-BR) from human pulmonary microvascular endothelial cells (HPMVECs) and monocytes, respectively. PlGF-mediated ET-1 and ET-BR expression occurred via activation of PI-3 kinase, reactive oxygen species and hypoxia inducible factor-1α (HIF-1α). PlGF increased binding of HIF-1α to the ET-1 and ET-BR promoters; this effect was abrogated with mutation of hypoxia response elements in the promoter regions and HIF-1α siRNA and confirmed by chromatin immunoprecipitation analysis. Furthermore, PlGF-mediated ET-1 release from HPMVECs and ET-BR expression in monocytes creates a PlGF–ET-1–ET-BR loop, leading to increased expression of MCP-1 and IL-8. Our studies show that PlGF-induced expression of the potent vasoconstrictor ET-1 and its cognate ET-BR receptor occur via activation of HIF-1α, independent of hypoxia. PlGF levels are intrinsically elevated from the increased red cell turnover in SCD and in other chronic anemia (eg, thalassemia) and may contribute to inflammation and PHT seen in these diseases.

Download Full-text

Vascular endothelial growth factor, placenta growth factor and their receptors in isolated human trophoblast

Placenta ◽

10.1016/s0143-4004(97)90007-2 ◽

1997 ◽

Vol 18 (8) ◽

pp. 657-665 ◽

Cited By ~ 223

Author(s):

V.H. Shore ◽

T.-H. Wang ◽

C.-L. Wang ◽

R.J. Torry ◽

M.R. Caudle ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Vascular Endothelial ◽

Placenta Growth Factor ◽

Human Trophoblast ◽

Endothelial Growth Factor

Download Full-text

Kinetics of Placenta Growth Factor/Vascular Endothelial Growth Factor Synergy in Endothelial Hydraulic Conductivity and Proliferation

Microvascular Research ◽

10.1006/mvre.2000.2298 ◽

2001 ◽

Vol 61 (2) ◽

pp. 203-210 ◽

Cited By ~ 19

Author(s):

Randal O. Dull ◽

J. Yuan ◽

Y.S. Chang ◽

J. Tarbell ◽

R.K. Jain ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Hydraulic Conductivity ◽

Vascular Endothelial ◽

Placenta Growth Factor ◽

Endothelial Growth Factor ◽

Kinetics Of

Download Full-text

Synthesis and physiological activity of heterodimers comprising different splice forms of vascular endothelial growth factor and placenta growth factor

Biochemical Journal ◽

10.1042/bj3160703 ◽

1996 ◽

Vol 316 (3) ◽

pp. 703-707 ◽

Cited By ~ 34

Author(s):

Ralf BIRKENHÄGER ◽

Bernard SCHNEPPE ◽

Wolfgang RÖCKL ◽

Jörg WILTING ◽

Herbert A. WEICH ◽

...

Keyword(s):

Endothelial Cells ◽

Growth Factor ◽

Vascular Endothelial Cells ◽

Physiological Activity ◽

Expression System ◽

Vascular Endothelial ◽

Placenta Growth Factor ◽

Splice Forms

Vascular endothilial growth factor (VEGF) and placenta growth factor (PIGF) are members of a dimeric-growth-factor family with angiogenic properties. VEGF is a highly potent and specific mitogen for endothelial cells, playing a vital role in angiogenesis in vivo. The role of PIGF is less clear. We expressed the monomeric splice forms VEGF-165, VEGF-121, PIGF-1 and PlGF-2 as unfused genes in Escherichia coli using the pCYTEXP expression system. In vitro dimerization experiments revealed that both homo- and hetero-dimers can be formed from these monomeric proteins. The dimers were tested for their ability to promote capillary growth in vivo and stimulate DNA synthesis in cultured human vascular endothelial cells. Heterodimers comprising different VEGF splice forms, or combinations of VEGF/PlGF splice forms, showed mitogenic activity. The results demonstrate that four different heterodimeric growth factors are likely to have as yet uncharacterized functions in vivo.

Download Full-text

Placenta Growth Factor (PlGF), a Novel Inducer of Plasminogen Activator Inhibitor-1 (PAI-1) in Sickle Cell Disease (SCD)

Journal of Biological Chemistry ◽

10.1074/jbc.m110.101691 ◽

2010 ◽

Vol 285 (22) ◽

pp. 16713-16722 ◽

Cited By ~ 25

Author(s):

Nitin Patel ◽

Nambirajan Sundaram ◽

Mingyan Yang ◽

Catherine Madigan ◽

Vijay K. Kalra ◽

...

Keyword(s):

Growth Factor ◽

Sickle Cell Disease ◽

Plasminogen Activator ◽

Sickle Cell ◽

Plasminogen Activator Inhibitor ◽

Cell Disease ◽

Placenta Growth Factor ◽

Plasminogen Activator Inhibitor 1 ◽

Activator Inhibitor ◽

Pai 1

Download Full-text

Vascular Endothelial Growth Factor and Placenta Growth Factor in Intrauterine Growth-Restricted Fetuses and Neonates

Mediators of Inflammation ◽

10.1155/mi.2005.293 ◽

2005 ◽

Vol 2005 (5) ◽

pp. 293-297 ◽

Cited By ~ 21

Author(s):

Ariadne Malamitsi-Puchner ◽

Theodora Boutsikou ◽

Emmanuel Economou ◽

Angeliki Sarandakou ◽

Evangelos Makrakis ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Intrauterine Growth Restriction ◽

Vascular Endothelial ◽

Placenta Growth Factor ◽

Placental Function ◽

Intrauterine Growth ◽

Appropriate For Gestational Age ◽

Endothelial Growth Factor ◽

Circulating Levels

The angiogenic factors vascular endothelial growth factor (VEGF) and placenta growth factor (PlGF) are respectively up- and downregulated by hypoxia. We aimed to study circulating levels of the above factors in intrauterine growth restriction (IUGR) and to correlate their levels with the customized centiles of the infants. The study included 25 IUGR and 25 appropriate for gestational age (AGA) full-term, singleton infants and their mothers. Maternal (MS), fetal (UC), and neonatal day 1 (N1) and 4 (N4) blood was examined. MS and N1 PlGF, as well as UC VEGF levels correlated with the customized centiles of the infants (r=0.39,P=.007,r=0.34,P=.01, andr=−0.41,P=.004, resp). Furthermore, UC, N1, and N4 VEGF levels were higher in girls (r=0.36,P=.01,r=0.33,P=.02, andr=0.41,P=.005resp). In conclusion, positive and negative correlations of examined factors with the customized centiles of the infant could rely on placental function and intrauterine oxygen concentrations—both being usually lower in IUGR cases—while higher VEGF levels in girls should possibly be attributed to the stimulating action of estrogens.

Download Full-text