Περίληψη:
Morbidelli L, Pyriochou A, Filippi S, Vasileiadis I, Roussos C, Zhou Z,
Loutrari H, Waltenberger J, Stossel A, Giannis A, Ziche M,
Papapetropoulos A. The soluble guanylyl cyclase inhibitor NS-2028
reduces vascular endothelial growth factor-induced angiogenesis and
permeability. Am J Physiol Regul Integr Comp Physiol 298: R824-R832,
2010. First published December 23, 2009;
doi:10.1152/ajpregu.00222.2009.-Nitric oxide (NO) is known to promote
vascular endothelial growth factor (VEGF)stimulated permeability and
angiogenesis. However, effector molecules that operate downstream of NO
in this pathway remain poorly characterized. Herein, we determined the
effect of soluble guanylyl cyclase (sGC) inhibition on VEGF responses in
vitro and in vivo. Treatment of endothelial cells (EC) with VEGF
stimulated eNOS phosphorylation and cGMP accumulation; pretreatment with
the sGC inhibitor
4H-8-bromo-1,2,4-oxadiazolo(3,4-d)benz(b)(1,4)oxazin-1-one (NS-2028)
blunted cGMP levels without affecting VEGF-receptor phosphorylation.
Incubation of cells with NS-2028 blocked the mitogenic effects of VEGF.
In addition, cells in which sGC was inhibited exhibited no migration and
sprouting in response to VEGF. To study the mechanisms through which
NS-2028 inhibits EC migration, we determined the effects of alterations
in cGMP levels on p38 MAPK. Initially, we observed that inhibition of
sGC attenuated VEGF-stimulated activation of p38. In contrast, the
addition of 8-Br-cGMP to EC stimulated p38 phosphorylation. The addition
of cGMP elevating agents (BAY 41-2272, DETA NO and YC-1) enhanced EC
migration. To test whether sGC also mediated the angiogenic effects of
VEGF in vivo, we used the rabbit cornea assay. Animals receiving NS-2028
orally displayed a reduced angiogenic response to VEGF. As increased
vascular permeability occurs prior to new blood vessel formation, we
determined the effect of NS-2028 in vascular leakage. Using a modified
Miles assay, we observed that NS-2028 attenuated VEGF-induced
permeability. Overall, we provide evidence that sGC mediates the
angiogenic and permeability-promoting activities of VEGF, indicating the
significance of sGC as a downstream effector of VEGF-triggered
responses.
Συγγραφείς:
Morbidelli, Lucia
Pyriochou, Anastasia
Filippi, Sandra and
Vasileiadis, Ioannis
Roussos, Charis
Zhou, Zongmin
Loutrari,
Heleni
Waltenberger, Johannes
Stoessel, Anne
Giannis,
Athanassios
Ziche, Marina
Papapetropoulos, Andreas
