e release of Ca2+ from intracellular stores is a key process involved in a variety of signaling pathways. e second messenger nicotinic acid adenine dinucleotide phosphate (NAADP) mobilizes Ca2+ from lysosomelike acidic stores but not from IP3-sensitive or ryanodine-sensitive Ca2+ stores in different cell types. To date, two receptors for NAADP have been discovered, namely TPC1 and TPC2. Interestingly, intracellular calcium dynamics plays a central role in angiogenesis of endothelial cells (EC) which is primarily triggered in response to growth factor such as vascular endothelial growth factor (VEGF). In addition to its well known role in the formation of new blood vessels, VEGF is also involved in a number of different EC functions such as proliferation, migration, regulation of vascular permeability and survival through the binding to two receptors (VEGFR1 and VEGFR2) both stimulating intracellular calcium mobilization. e aim of our study is to characterize the role of Ca2+ in VEGF-dependent signal transduction and to correlate its intracellular signaling to specific biological functions. Our data propose the involvement of NAADP in VEGFR2- but not VEGFR1-induced calcium mobilization. We show that both pharmacological inhibition of NAADP signaling with Ned-19 (a reported specific antagonist of NAADP) and the use of small interfering RNA (siRNA) targeting TPC1 and TPC2, significantly reduces VEGF-stimulated calcium release in Human Umbilical Vein Endothelial Cells (HUVEC). Our data suggest that both Ned-19 and silencing of TPC receptors by RNAi down regulates VEGF-stimulated ERK1/2 phosphorilation. Moreover, we observed that Ned-19 modulates Akt activation and inhibits VEGF-induced migration of EC. All together our data suggest that NAADP plays an important role in VEGF-induced Ca2+ signaling via tyrosine kinase receptor and open new strategies for studying EC functions.
|Titolo della pubblicazione ospite||ABCD 2011 Congress|
|Numero di pagine||1|
|Stato di pubblicazione||Pubblicato - 2011|
|Evento||ABCD 2011 Congress 08-10 Settembre 2011 - Ravenna|
Durata: 8 set 2011 → 10 set 2011
|Convegno||ABCD 2011 Congress 08-10 Settembre 2011|
|Periodo||8/9/11 → 10/9/11|