Microvascular Notch Signaling Is Upregulated in Response to Vascular Endothelial Growth Factor and Chronic Myocardial Ischemia

Lassaletta, Antonio D.; Elmadhun, Nassrene Y.; Burgess, T.; Bianchi, Cesario; Sabe, Ashraf A.; Robich, Michael P.; Chu, Louis M.; Sellke, Frank W.

doi:10.1253/circj.cj-13-0685

Cited by 11 publications

(7 citation statements)

References 29 publications

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“…Although we previously reported that there was no difference in cardiac function, perhaps long-term MetS-mediated cell death may result in decreased contractility and reduced adaptability to myocardial ischemia. 8 Our finding of decreased Notch signaling in this early stage MetS is consistent with these molecular signals being causally related to decreased angiogenesis in later stage MetS. 24 …”

Section: Discussionsupporting

confidence: 74%

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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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Section: Discussionsupporting

confidence: 74%

“…8 The Notch signaling pathway is an evolutionarily conserved pathway that is important for many processes including cell fate determination differentiation, proliferation, apoptosis, and regeneration. 9 Studies have shown that postnatal Notch signaling is critical for angiogenesis.…”

Section: Introductionmentioning

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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“…In mouse heart, Notch1 activation by intramyocardial delivery of a monoclonal antibody (pseudo-ligand), 4 weeks after infarction, led to higher levels of angiogenesis markers, which were associated to reduced scar and improved cardiac functions ( 113 ). VEGF administration to chronically ischemic myocardium results in an upregulation of several Notch receptors and ligands and increased capillary and arteriolar density compared with ischemia alone ( 128 ). Similarly, transplantation of Dll4 overexpressing EPCs increases the blood flow to the ischemic zone and improves cardiac function ( 129 ).…”

Section: Role Of Notch In Cardiovascular Systemmentioning

confidence: 99%

The Role of Notch in the Cardiovascular System: Potential Adverse Effects of Investigational Notch Inhibitors

Rizzo

Mele²,

Caliceti

et al. 2015

Front. Oncol.

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Targeting the Notch pathway is a new promising therapeutic approach for cancer patients. Inhibition of Notch is effective in the oncology setting because it causes a reduction of highly proliferative tumor cells and it inhibits survival of cancer stem cells, which are considered responsible for tumor recurrence and metastasis. Additionally, since Delta-like ligand 4 (Dll4)-activated Notch signaling is a major modulator of angiogenesis, anti-Dll4 agents are being investigated to reduce vascularization of the tumor. Notch plays a major role in the heart during the development and, after birth, in response to cardiac damage. Therefore, agents used to inhibit Notch in the tumors (gamma secretase inhibitors and anti-Dll4 agents) could potentially affect myocardial repair. The past experience with trastuzumab and other tyrosine kinase inhibitors used for cancer therapy demonstrates that the possible cardiotoxicity of agents targeting shared pathways between cancer and heart and the vasculature should be considered. To date, Notch inhibition in cancer patients has resulted only in mild gastrointestinal toxicity. Little is known about the potential long-term cardiotoxicity associated to Notch inhibition in cancer patients. In this review, we will focus on mechanisms through which inhibition of Notch signaling could lead to cardiomyocytes and endothelial dysfunctions. These adverse effects could contrast with the benefits of therapeutic responses in cancer cells during times of increased cardiac stress and/or in the presence of cardiovascular risk factor.

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“…Furthermore, VEGF contributes to postnatal neovascularization by mobilizing EPCs [12]. In previous studies of mammalian endothelial cells, Notch signals were induced by downstream signals of the VEGF receptor [43]. In contrast, it was recently reported that Jagged-1 and Jagged-2 increase VEGF secretion, and that Notch1 activates hypoxia-inducible factor-1α, the main regulator of VEGF in cancer angiogenesis [36].…”

Section: Discussionmentioning

confidence: 99%

Jagged-1 Signaling in the Bone Marrow Microenvironment Promotes Endothelial Progenitor Cell Expansion and Commitment of CD133+ Human Cord Blood Cells for Postnatal Vasculogenesis

Ishige-Wada¹,

Kwon²,

Eguchi³

et al. 2016

PLoS ONE

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Notch signaling is involved in cell fate decisions during murine vascular development and hematopoiesis in the microenvironment of bone marrow. To investigate the close relationship between hematopoietic stem cells and human endothelial progenitor cells (EPCs) in the bone marrow niche, we examined the effects of Notch signals [Jagged-1 and Delta-like ligand (Dll)-1] on the proliferation and differentiation of human CD133+ cell-derived EPCs. We established stromal systems using HESS-5 murine bone marrow cells transfected with human Jagged-1 (hJagged-1) or human Dll-1 (hDll-1). CD133+ cord blood cells were co-cultured with the stromal cells for 7 days, and then their proliferation, differentiation, and EPC colony formation was evaluated. We found that hJagged-1 induced the proliferation and differentiation of CD133+ cord blood EPCs. In contrast, hDll-1 had little effect. CD133+ cells stimulated by hJagged-1 differentiated into CD31+/KDR+ cells, expressed vascular endothelial growth factor-A, and showed enhanced EPC colony formation compared with CD133+ cells stimulated by hDll-1. To evaluate the angiogenic properties of hJagged-1- and hDll-1-stimulated EPCs in vivo, we transplanted these cells into the ischemic hindlimbs of nude mice. Transplantation of EPCs stimulated by hJagged-1, but not hDll-1, increased regional blood flow and capillary density in ischemic hindlimb muscles. This is the first study to show that human Notch signaling influences EPC proliferation and differentiation in the bone marrow microenvironment. Human Jagged-1 induced the proliferation and differentiation of CD133+ cord blood progenitors compared with hDll-1. Thus, hJagged-1 signaling in the bone marrow niche may be used to expand EPCs for therapeutic angiogenesis.

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Microvascular Notch Signaling Is Upregulated in Response to Vascular Endothelial Growth Factor and Chronic Myocardial Ischemia

Cited by 11 publications

References 29 publications

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

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

The Role of Notch in the Cardiovascular System: Potential Adverse Effects of Investigational Notch Inhibitors

Jagged-1 Signaling in the Bone Marrow Microenvironment Promotes Endothelial Progenitor Cell Expansion and Commitment of CD133+ Human Cord Blood Cells for Postnatal Vasculogenesis

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