scholarly journals Mathematical Model Predicts Effective Strategies to Inhibit VEGF-eNOS Signaling

2020 ◽  
Vol 9 (5) ◽  
pp. 1255
Author(s):  
Qianhui Wu ◽  
Stacey D. Finley
Keyword(s):  
Nitric Oxide ◽  
Signaling Pathway ◽  
Tumor Angiogenesis ◽  
Mechanistic Model ◽  
Angiogenesis Inhibitors ◽  
Effective Strategies ◽  
Angiogenic Inhibitor ◽  
Oxide Synthase ◽  
Endothelial Growth Factor ◽  
Endothelial Nitric Oxide

The endothelial nitric oxide synthase (eNOS) signaling pathway in endothelial cells has multiple physiological significances. It produces nitric oxide (NO), an important vasodilator, and enables a long-term proliferative response, contributing to angiogenesis. This signaling pathway is mediated by vascular endothelial growth factor (VEGF), a pro-angiogenic species that is often targeted to inhibit tumor angiogenesis. However, inhibiting VEGF-mediated eNOS signaling can lead to complications such as hypertension. Therefore, it is important to understand the dynamics of eNOS signaling in the context of angiogenesis inhibitors. Thrombospondin-1 (TSP1) is an important angiogenic inhibitor that, through interaction with its receptor CD47, has been shown to redundantly inhibit eNOS signaling. However, the exact mechanisms of TSP1′s inhibitory effects on this pathway remain unclear. To address this knowledge gap, we established a molecular-detailed mechanistic model to describe VEGF-mediated eNOS signaling, and we used the model to identify the potential intracellular targets of TSP1. In addition, we applied the predictive model to investigate the effects of several approaches to selectively target eNOS signaling in cells experiencing high VEGF levels present in the tumor microenvironment. This work generates insights for pharmacologic targets and therapeutic strategies to inhibit tumor angiogenesis signaling while avoiding potential side effects in normal vasoregulation.

scholarly journals p32-Dependent p38 MAPK Activation by Arginase II Downregulation Contributes to Endothelial Nitric Oxide Synthase Activation in HUVECs

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 392 ◽  
Author(s):  
Bon-Hyeock Koo ◽  
Moo-Ho Won ◽  
Young-Myeong Kim ◽  
Sungwoo Ryoo
Keyword(s):  
Nitric Oxide ◽  
Signaling Pathway ◽  
P38 Mapk ◽  
Endothelial Nitric Oxide Synthase ◽  
Oxygen Species ◽  
Mapk Activation ◽  
Enos Phosphorylation ◽  
Arginase Ii ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Arginase II reciprocally regulates endothelial nitric oxide synthase (eNOS) through a p32-dependent Ca2+ control. We investigated the signaling pathway of arginase II-dependent eNOS phosphorylation. Western blot analysis was applied for examining protein activation and [Ca2+]c was analyzed by microscopic and FACS analyses. Nitric oxide (NO) and reactive oxygen species (ROS) productions were measured using specific fluorescent dyes under microscopy. NO signaling pathway was tested by measuring vascular tension. Following arginase II downregulation by chemical inhibition or gene knockout (KO, ArgII−/−), increased eNOS phosphorylation at Ser1177 and decreased phosphorylation at Thr495 was depend on p38 MAPK activation, which induced by CaMKII activation through p32-dependent increase in [Ca2+]c. The protein amount of p32 negatively regulated p38 MAPK activation. p38 MAPK contributed to Akt-induced eNOS phosphorylation at Ser1177 that resulted in accelerated NO production and reduced reactive oxygen species production in aortic endothelia. In vascular tension assay, p38 MAPK inhibitor decreased acetylcholine-induced vasorelaxation responses and increased phenylephrine-dependent vasoconstrictive responses. In ApoE−/− mice fed a high cholesterol diet, arginase II inhibition restored p32/CaMKII/p38 MAPK/Akt/eNOS signaling cascade that was attenuated by p38 MAPK inhibition. Here, we demonstrated a novel signaling pathway contributing to understanding of the relationship between arginase II, endothelial dysfunction, and atherogenesis.

scholarly journals Endothelial Dysfunction in Breast Cancer In-Vivo Model

Proceedings ◽  
2018 ◽  
Vol 2 (25) ◽  
pp. 1536
Author(s):  
Buğra Elkar ◽  
Mustafa Barış ◽  
Meryem Çalışır ◽  
Yasemin Çakır ◽  
Safiye Aktaş ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Dysfunction ◽  
Nitric Oxide Synthase ◽  
Endothelial Nitric Oxide Synthase ◽  
Growth Factor Receptor ◽  
Vascular Endothelial ◽  
Vascular Endothelial Cadherin ◽  
Oxide Synthase ◽  
Endothelial Growth Factor ◽  
Endothelial Nitric Oxide

Although the endothelial dysfunction is related with tumor development, there is no consensus on the suppressive or supportive effect on tumor growth. The goal of the present study was to evaluate endothelial dysfunction related factors in animal breast cancer model that was developed by administrating endothelial nitric oxide synthase blocking agent, Nitro-L-arginine methyl ester hydrochloride (L-NAME). Endothelial dysfunction related main factors such as nitric oxide synthase, interleukin-6, vascular endothelial growth factor receptor-2 and vascular endothelial cadherin were investigated by immunohistochemically in tumor and carotid artery tissues. In tumor tissues apoptosis was determined by TUNEL assay. The level of endothelin-1 in blood was measured by ELISA. İntima-media thickness of carotid artery was evaluated with Doppler-USG measurements. As a result, in this study it was shown that vascular endothelial growth factor receptor-2, endothelin-1, endothelial nitric oxide synthase, interleukin-6, vascular endothelial cadherin and E-selectin molecules play a role in reducing breast tumor growth based on endothelial dysfunction.

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