Prostaglandins induce vascular endothelial growth factor in a human monocytic cell line and rat lungs via cAMP.
Prostaglandins have emerged as a therapeutic option for patients with peripheral vascular disease as well as pulmonary hypertension as a means to increase blood flow. We tested the hypothesis that prostaglandins regulate vascular endothelial growth factor (VEGF) expression in the human monocytic THP-1 cell line and in isolated perfused rat lungs. Our data show that the stable PGI2-analogue iloprost induces VEGF gene expression (predominantly VEGF121, but also VEGF165 isoforms) and VEGF protein synthesis in THP-1 cells. This effect is abolished by dexamethasone and by Rp-cAMP, a specific inhibitor of cAMP-dependent protein kinase (PKA) activation. The calcium channel blocker diltiazem has no effect on the iloprost-induced VEGF gene expression, and depletion of intracellular Ca2+ stores by long-term exposure (16 h) of THP-1 cells to thapsigargin does not inhibit iloprost-induced VEGF gene expression, suggesting that an increase in intracellular Ca2+ is not essential for VEGF gene induction by iloprost. However, an increase of intracellular Ca2+ by a short-term (2 h) exposure of THP-1 cells to thapsigargin or to the calcium-ionophore A23187 increases VEGF mRNA levels, indicating that a change in intracellular Ca2+ by itself can alter VEGF gene expression. The effects of thapsigargin or A23187 on VEGF gene expression are also mediated via cAMP-PKA since they are inhibited by Rp-cAMP. In isolated perfused rat lungs, PGI2 and PGE2 increases VEGF mRNA abundance whereas Rp-cAMP inhibits the prostaglandin-induced VEGF gene activation. Thus, our data suggest that prostaglandins stimulate VEGF gene expression in monocytic cells and in rat lungs via a cAMP-dependent mechanism.
Höper
M M
MM
Department of Pathology, Pulmonary Hypertension Center, and University of Colorado Health Sciences Center, Denver 80262, USA.
Voelkel
N F
NF
Bates
T O
TO
Allard
J D
JD
Horan
M
M
Shepherd
D
D
Tuder
R M
RM
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D016228:Endothelial Growth Factors / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008222:Lymphokines / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D011453:Prostaglandins / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015533:Transcriptional Activation; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; D011453:Prostaglandins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D002118:Calcium