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The Soluble Guanylyl Cyclase Inhibitor NS-2028 Reduces Vascular Endothelial Growth Factor-Induced Angiogenesis and Permeability

The Soluble Guanylyl Cyclase Inhibitor NS-2028 Reduces Vascular Endothelial Growth Factor-Induced Angiogenesis and Permeability

Lucia Morbidelli, Anastasia Pyriochou, Sandra Filippi, Ioannis Vasileiadis, Charis Roussos, Zongmin Zhou, Heleni Loutrari, Johannes Waltenberger, Anne Stössel, Athanassios Giannis, Marina Ziche, Andreas Papapetropoulos

Am J Physiol Regul Integr Comp Physiol. 2010 Mar;298(3):R824-32.

PMID: 20032260

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP204326432	NS 2028		204326-43-2	Price

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