Journal Article

Phorbol esters induce PLVAP expression via VEGF and additional secreted molecules in MEK1‐dependent and p38, JNK and PI3K/Akt‐independent manner

Hamilton, B. JoNell, Tse, Dan, Stan, Radu V.

2019

Overview

Endothelial diaphragms are subcellular structures critical for mammalian survival with poorly understood biogenesis. Plasmalemma vesicle associated protein (PLVAP) is the only known diaphragm component and is necessary for diaphragm formation. Very little is known about PLVAP regulation. Phorbol esters (PMA) are known to induce de novo PLVAP expression and diaphragm formation. We show that this induction relies on the de novo production of soluble factors that will act in an autocrine manner to induce PLVAP transcription and protein expression. We identified vascular endothelial growth factor‐A (VEGF‐A) signalling through VEGFR2 as a necessary but not sufficient downstream event as VEGF‐A inhibition with antibodies and siRNA or pharmacological inhibition of VEGFR2 only partially inhibit PLVAP upregulation. In terms of downstream pathways, inhibition of MEK1/Erk1/2 MAP kinase blocked PLVAP upregulation, whereas inhibition of p38 and JNK MAP kinases or PI3K and Akt had no effect on PMA‐induced PLVAP expression. In conclusion, we show that VEGF‐A along with other secreted proteins act synergistically to up‐regulate PLVAP in MEK1/Erk1/2 dependent manner, bringing us one step further into understanding the genesis of the essential structures that are endothelial diaphragms.

• Publisher: John Wiley and Sons Inc
• Subject: Anthracenes - pharmacology / Autocrine Communication - genetics / Axitinib - pharmacology / Butadienes - pharmacology / cancer / caveolae / diapedesis / endothelial diaphragm / fenestrae / Flavonoids - pharmacology / Gene Expression Regulation / Human Umbilical Vein Endothelial Cells - cytology / Human Umbilical Vein Endothelial Cells - drug effects / Human Umbilical Vein Endothelial Cells - metabolism / Humans / Imidazoles - pharmacology / Indazoles - pharmacology / inflammation / MAP Kinase Kinase 1 - antagonists & inhibitors / MAP Kinase Kinase 1 - genetics / MAP Kinase Kinase 1 - metabolism / MAP Kinase Kinase 4 - antagonists & inhibitors / MAP Kinase Kinase 4 - genetics / MAP Kinase Kinase 4 - metabolism / Membrane Proteins - agonists / Membrane Proteins - genetics / Membrane Proteins - metabolism / Nitriles - pharmacology / Original / permeability / Phosphatidylinositol 3-Kinases - genetics / Phosphatidylinositol 3-Kinases - metabolism / Piperazines - pharmacology / Protein Kinase Inhibitors - pharmacology / Proto-Oncogene Proteins c-akt - antagonists & inhibitors / Proto-Oncogene Proteins c-akt - genetics / Proto-Oncogene Proteins c-akt - metabolism / Pyridines - pharmacology / Pyrimidines - pharmacology / RNA, Small Interfering - genetics / RNA, Small Interfering - metabolism / Signal Transduction / Sulfonamides - pharmacology / Tetradecanoylphorbol Acetate - pharmacology / transendothelial channel / Vascular Endothelial Growth Factor A - antagonists & inhibitors / Vascular Endothelial Growth Factor A - genetics / Vascular Endothelial Growth Factor A - metabolism / Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors / Vascular Endothelial Growth Factor Receptor-2 - genetics / Vascular Endothelial Growth Factor Receptor-2 - metabolism / VVO