Open AccessPhorbol esters induce PLVAP expression via VEGF and additional secreted molecules in MEK 1‐dependent and p38, JNK and PI 3K/Akt‐independent manner
Author(s) -
Hamilton B. JoNell,
Tse Dan,
Stan Radu V.
Publication year - 2019
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.13993
Subject(s) - microbiology and biotechnology , downregulation and upregulation , autocrine signalling , chemistry , p38 mitogen activated protein kinases , biology , mapk/erk pathway , kinase , biochemistry , receptor , gene
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 VEGFR 2 as a necessary but not sufficient downstream event as VEGF ‐A inhibition with antibodies and si RNA or pharmacological inhibition of VEGFR 2 only partially inhibit PLVAP upregulation. In terms of downstream pathways, inhibition of MEK 1/Erk1/2 MAP kinase blocked PLVAP upregulation, whereas inhibition of p38 and JNK MAP kinases or PI 3K 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 MEK 1/Erk1/2 dependent manner, bringing us one step further into understanding the genesis of the essential structures that are endothelial diaphragms.