Gamma-Secretase Inhibitor Treatment Promotes VEGF-A-Driven Blood Vessel Growth and Vascular Leakage but Disrupts Neovascular Perfusion

Abstract

The Notch signaling pathway is essential for normal development due to its role in control of cell differentiation, proliferation and survival. It is also critically involved in tumorigenesis and cancer progression. A key enzyme in the activation of Notch signaling is the gamma-secretase protein complex and therefore, gamma-secretase inhibitors (GSIs)—originally developed for Alzheimer's disease—are now being evaluated in clinical trials for human malignancies. It is also clear that Notch plays an important role in angiogenesis driven by Vascular Endothelial Growth Factor A (VEGF-A)—a process instrumental for tumor growth and metastasis. The effect of GSIs on tumor vasculature has not been conclusively determined. Here we report that Compound X (CX), a GSI previously reported to potently inhibit Notch signaling in vitro and in vivo, promotes angiogenic sprouting in vitro and during developmental angiogenesis in mice. Furthermore, CX treatment suppresses tumor growth in a mouse model of renal carcinoma, leads to the formation of abnormal vessels and an increased tumor vascular density. Using a rabbit model of VEGF-A-driven angiogenesis in skeletal muscle, we demonstrate that CX treatment promotes abnormal blood vessel growth characterized by vessel occlusion, disrupted blood flow, and increased vascular leakage. Based on these findings, we propose a model for how GSIs and other Notch inhibitors disrupt tumor blood vessel perfusion, which might be useful for understanding this new class of anti-cancer agents.

Inhibition of Notch signaling induces extensive intussusceptive neo-angiogenesis by recruitment of mononuclear cells

“…Despite the observed significant angiogenic activity under Notch inhibition, the authors mentioned here above nicely documented reduced mural cell coverage. Endothelial protrusions in the vessel lumen and intraluminal vessel occlusions were positive for endothelial markers [38], but the authors failed to attribute this effect to the induced intussusceptive angiogenesis. Careful look at the vascular pattern behind the invading sprouting vessels demonstrated that in already formed vascular bed, Notch inhibition led to IA, which is a complementary mechanism of angiogenesis.…”

Amyloid-β Increases Capillary Bed Density in the Adult Zebrafish Retina

“…5 As a physiological c-secretase inhibitor, Ab may promote VEGF signaling and disrupt neovascular perfusion. 29 These effects could be differentially impacted by ApoE alleles as this cholesterol chaperone is produced by pericytes that surround capillary endothelial cells and may affect the integrity of blood capillaries in the brain. 30 Anti-Ab therapy has been shown to protect RPE and prevent vision loss in an AMD mouse model 22,31 and to improve cognition in mouse models for AD.…”

Notch Signaling in Ocular Vasculature Development and Diseases

“…Although the precise mechanisms of Notch signaling are far from being fully illustrated at each stage of angiogenesis, the identification of the Notch signal in tip cell selection, endothelial quiescence, vessel maturation and EPC mobilization and function makes it a prospective candidate for angiogenic therapies ( Figure 2). A number of approaches are available or potentially possible to modulate Notch signaling at different levels of the angiogenic cascade, including antibody antagonists (33,71), antisense or interfering RNA (107), soluble ligands and receptor decoys (33,71) and inhibitors of the enzymes involved in glycosylation or cleavage of receptors, such as γ-secretase or ADAM inhibitors (108).…”