Related Experiment Video
Updated: May 25, 2026
06:51
A Patient-Derived Xenograft Model for Venous Malformation
Published on: June 15, 2020
Notch4 normalization reduces blood vessel size in arteriovenous malformations
Patrick A Murphy1, Tyson N Kim, Gloria Lu
1Laboratory for Accelerated Vascular Research, Division of Vascular Surgery, Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA.
Science Translational Medicine
|January 21, 2012
Summary
Normalizing Notch signaling reversed enlarged blood vessels in mouse brains. This targeted therapy regressed arteriovenous (AV) shunts, restoring capillary blood flow and potentially treating AVMs.
Area of Science:
- Vascular Biology
- Molecular Signaling
- Regenerative Medicine
Background:
- Arteriovenous malformations (AVMs) involve enlarged blood vessels and high-flow arteriovenous (AV) shunts, disrupting normal circulation.
- These shunts divert blood from capillaries, leading to tissue hypoxia and potentially life-threatening conditions.
Purpose of the Study:
- To investigate the role of Notch signaling in the development of AV shunts in the mouse brain.
- To determine if normalizing Notch signaling can reverse established AV shunts and restore normal blood flow.
Main Methods:
- Utilized transgenic mice with constitutively active Notch4 (Notch4*) to induce AV shunts in endothelial cells (ECs).
- Employed four-dimensional two-photon imaging through a cranial window for real-time observation of vascular dynamics.
- Manipulated Notch signaling by repressing Notch4* expression to assess its effect on AV shunt regression.
Main Results:
- Repressing Notch4* normalized Notch signaling, converting high-flow AV shunts into capillary-like vessels.
- Vessel regression occurred through narrowing without endothelial cell loss, dependent on EphB4 receptor restoration.
- Restoration of normal blood flow to capillaries reversed tissue hypoxia.
Conclusions:
- Normalization of Notch signaling effectively regresses high-flow AV shunts, suggesting a therapeutic avenue.
- Targeting the Notch pathway may offer a novel treatment strategy for AVMs and related vascular disorders.
- EphB4 receptor signaling is crucial for the regression of AV shunts following Notch pathway modulation.
Related Concept Videos
03:14Notch Signaling Pathway
The Notch signaling pathway is a major intracellular signaling pathway that is highly conserved over a broad spectrum of metazoan species. It stands unique from other intracellular signaling mechanisms in animals because notch protein itself acts as the receptor as well as the primary signaling molecule.
The Notch gene came into the limelight in 1914 after the discovery that its mutation in Drosophila melanogaster leads to a serrated (or "notched") wing margin phenotype. It was not until 1985...
The Notch gene came into the limelight in 1914 after the discovery that its mutation in Drosophila melanogaster leads to a serrated (or "notched") wing margin phenotype. It was not until 1985...
01:24Regulation of Angiogenesis and Blood Supply
Rapidly dividing tumors, embryos, and wounded tissues require more oxygen than usual, lowering the oxygen concentration in the blood. At low oxygen or hypoxic conditions, an oxygen-sensitive transcription factor called the hypoxia-inducible factor 1 or HIF1 is activated. HIF1 is a dimeric protein of alpha (ɑ) and beta (β) subunits. Under optimal oxygen conditions, HIF1β is present in the nucleus while HIF1ɑ remains in the cytosol. HIF1ɑ is hydroxylated by prolyl hydroxylase and factor...
01:17Autoregulation of Blood Flow
Autoregulation mechanisms are characterized by their inherent capacity for self-regulation without necessitating specific nervous stimulation or endocrine control. These mechanisms facilitate the adjustment of blood flow and, therefore, perfusion specific to each tissue region. This self-regulation encompasses chemical signals and myogenic controls.
Chemical Signaling in Autoregulation
Chemical signaling operates at the precapillary sphincter level, inciting either contraction or relaxation.
Chemical Signaling in Autoregulation
Chemical signaling operates at the precapillary sphincter level, inciting either contraction or relaxation.
01:10Mechanism of Angiogenesis
Blood vessel formation starts early during embryonic development, around day 7. In the extraembryonic yolk sac, mesodermal precursor cells called hemangioblast proliferate and differentiate into angioblast. Angioblasts express vascular endothelial growth factor receptor 2 or VEGFR2, which binds VEGF-A, a proangiogenic factor, guiding blood vessel formation. VEGF signaling promotes angioblasts to form a blood island in the developing embryo. Angioblasts further differentiate, giving rise to...