Notch-Dependent Regulation of the Ischemic Vasodilatory Response—Brief Report

Chang, Alex Chia Yu; Patenaude, Alexandre; Lu, Katherine; Fuller, Megan; Ly, Michelle; Kyle, Alastair H.; Golbidi, Saeid; Wang, Yingjin; Walley, Keith R.; Minchinton, Andrew I.; Laher, Ismail; Karsan, Aly

doi:10.1161/atvbaha.112.300840

Cited by 13 publications

(15 citation statements)

References 12 publications

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“…9). dnMAML has been used to assess the effect of pan-inhibition of Notch signaling used in various vascular models, and although found to be specifically inhibitory to Notch signaling (22)(23)(24)(25)(26), one cannot entirely rule out the possibility that some unknown pathway is also impacted. We hypothesized that increasing VEGFA signaling would sensitize tumors to Notch inhibition, as VEGFA activates endothelial cell Notch signaling by increasing Dll4 expression in tip cells (12)(13)(14)27).…”

Section: Resultsmentioning

confidence: 99%

Endothelial-Specific Notch Blockade Inhibits Vascular Function and Tumor Growth through an eNOS-Dependent Mechanism

et al. 2014

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Notch signaling is important for tumor angiogenesis induced by vascular endothelial growth factor A. Blockade of the Notch ligand Dll4 inhibits tumor growth in a paradoxical way. Dll4 inhibition increases endothelial cell sprouting, but vessels show reduced perfusion. The reason for this lack of perfusion is not currently understood. Here we report that inhibition of Notch signaling in endothelial cell using an inducible binary transgenic system limits VEGFAdriven tumor growth and causes endothelial dysfunction. Neither excessive endothelial cell sprouting nor defects of pericyte abundance accompanied the inhibition of tumor growth and functional vasculature. However, biochemical and functional analysis revealed that endothelial nitric oxide production is decreased by Notch inhibition. Treatment with the soluble guanylate cyclase activator BAY41-2272, a vasorelaxing agent that acts downstream of endothelial nitric oxide synthase (eNOS) by directly activating its soluble guanylyl cyclase receptor, rescued blood vessel function and tumor growth. We show that reduction in nitric oxide signaling is an early alteration induced by Notch inhibition and suggest that lack of functional vessels observed with Notch inhibition is secondary to inhibition of nitric oxide signaling. Coculture and tumor growth assays reveal that Notch-mediated nitric oxide production in endothelial cell requires VEGFA signaling. Together, our data support that eNOS inhibition is responsible for the tumor growth and vascular function defects induced by endothelial Notch inhibition. This study uncovers a novel mechanism of nitric oxide production in endothelial cells in tumors, with implications for understanding the peculiar character of tumor blood vessels. Cancer Res; 74(9); 2402-11. Ó2014 AACR.

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Section: Resultsmentioning

confidence: 99%

Endothelial-Specific Notch Blockade Inhibits Vascular Function and Tumor Growth through an eNOS-Dependent Mechanism

et al. 2014

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“…In contrast, loss of blood flow led to increased vascular Notch signalling in the vasculature of zebrafish embryos63. Notch facilitates vessel constriction during the regression (pruning) of capillaries64, but Notch activity is also required for nitric oxide induction and vasodilation in response to ischaemia in the adult vasculature65. Furthermore, Notch activation is a hallmark of arteriovenous malformations and constitutive activation of Notch4 has been shown to induce the enlargement of capillary vessels into arteriovenous shunts66.…”

Section: Discussionmentioning

confidence: 99%

Blood flow controls bone vascular function and osteogenesis

et al. 2016

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While blood vessels play important roles in bone homeostasis and repair, fundamental aspects of vascular function in the skeletal system remain poorly understood. Here we show that the long bone vasculature generates a peculiar flow pattern, which is important for proper angiogenesis. Intravital imaging reveals that vessel growth in murine long bone involves the extension and anastomotic fusion of endothelial buds. Impaired blood flow leads to defective angiogenesis and osteogenesis, and downregulation of Notch signalling in endothelial cells. In aged mice, skeletal blood flow and endothelial Notch activity are also reduced leading to decreased angiogenesis and osteogenesis, which is reverted by genetic reactivation of Notch. Blood flow and angiogenesis in aged mice are also enhanced on administration of bisphosphonate, a class of drugs frequently used for the treatment of osteoporosis. We propose that blood flow and endothelial Notch signalling are key factors controlling ageing processes in the skeletal system.

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“…Previous studies have demonstrated a direct link between Notch signaling and eNOS activity. 18, 19 Notch activation activates eNOS, which induces NO synthesis. In an animal model of hindlimb ischemia, Notch inhibition in endothelial cells reduced reperfusion and NO generation.…”

Section: Discussionmentioning

confidence: 99%

“…In an animal model of hindlimb ischemia, Notch inhibition in endothelial cells reduced reperfusion and NO generation. 18 Ang1 is an angiogenic factor that also activates the pro-survival signaling pathway and initiates stem cell homing in the setting of myocardial ischemia. 20 In a porcine model of myocardial infarction, co-expression of VEGF and Ang1 was shown to increase angiogenesis, myocardial perfusion, and cardiomyocyte proliferation in ischemic myocardium.…”

Section: Discussionmentioning

confidence: 99%

Metabolic syndrome impairs notch signaling and promotes apoptosis in chronically ischemic myocardium

Elmadhun

Sabe

Lassaletta

et al. 2014

The Journal of Thoracic and Cardiovascular Surgery

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Objective Impaired angiogenesis is a known consequence of metabolic syndrome (MetS), however, the mechanism is not fully understood. Recent studies have shown that the Notch signaling pathway is an integral component of cardiac angiogenesis. We tested in a clinically relevant swine model the effects of MetS on Notch and apoptosis signaling in chronically ischemic myocardium. Methods Ossabaw swine were fed either a regular diet (CTL, n=8) or a high-cholesterol diet (MetS, n=8) to induce MetS. An ameroid constrictor was placed to induce chronic myocardial ischemia. Eleven weeks later, animals underwent cardiac harvest of the ischemic myocardium. Results There was down-regulation of pro-angiogenesis proteins Notch2, Notch4, Jagged2, Ang1 and ENOS in the MetS group compared to CTL. There was also up-regulation of pro-apoptosis protein Caspase8, and down-regulation of anti-angiogenesis protein pFOX03, and pro-survival proteins pP38 and HSP90 in the MetS group. Cell death was increased in the MetS group compared to CTL. Both CTL and MetS groups had similar arteriolar count and capillary density, and Notch3 and Jagged1 were both similarly concentrated in the smooth muscle wall in both groups. Conclusions MetS in chronic myocardial ischemia significantly impairs Notch signaling by down regulating Notch receptors, ligands and pro-angiogenesis proteins. MetS also increases apoptosis signaling, decreases survival signaling and increases cell death in chronically ischemic myocardium. Although short-term angiogenesis appears unaffected in this model of early MetS, the molecular signals for angiogenesis are impaired, thus suggesting that inhibition of Notch signaling may underlie decreased angiogenesis in later stages of MetS.

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Notch-Dependent Regulation of the Ischemic Vasodilatory Response—Brief Report

Cited by 13 publications

References 12 publications

Endothelial-Specific Notch Blockade Inhibits Vascular Function and Tumor Growth through an eNOS-Dependent Mechanism

Endothelial-Specific Notch Blockade Inhibits Vascular Function and Tumor Growth through an eNOS-Dependent Mechanism

Blood flow controls bone vascular function and osteogenesis

Metabolic syndrome impairs notch signaling and promotes apoptosis in chronically ischemic myocardium

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