Notch Signaling in Vascular Biology

Notch signalling is a highly conserved cell-to-cell communication pathway that governs vascular development, homeostasis and pathology. Four Notch receptors (Notch1–4) engage with membrane-bound ligands (Delta-like and Jagged families) on neighbouring cells to trigger proteolytic cleavage and release of an intracellular domain that regulates transcription. During embryogenesis this mechanism establishes arterial–venous identity and orchestrates angiogenic sprouting by balancing tip and stalk endothelial cell behaviour. In adult vessels Notch modulates endothelial proliferation, differentiation and barrier function in response to shear stress, hypoxia and inflammatory cues. Crosstalk with vascular endothelial growth factor, transforming growth factor-β and mechanotransduction pathways ensures adaptive remodelling under physiological and pathological conditions. Dysregulated Notch activity contributes to tumour angiogenesis, atherosclerosis, neointimal hyperplasia and vascular malformations, making its components attractive targets for regenerative medicine and vascular disease therapy.

Research from Nature Portfolio

Recent studies have demonstrated that endothelial Notch1 activation by laminar shear stress directs arteriolar remodelling and preserves barrier integrity under hypertensive challenges, revealing a protective role in flow adaptation. Investigations into spatial patterning of Delta-like 4 (DLL4) have shown how ligand gradients specify tip-cell selection during ischaemia-driven angiogenesis, with computational modelling predicting microvascular network architecture. Additionally, mechanobiological investigations have uncovered a feedback loop whereby Notch-dependent modulation of VE-cadherin junctions adjusts cytoskeletal tension to stabilise nascent vessels in both developmental and reparative contexts.

Notch Signaling in Vascular Biology publication trend

The graph below shows the total number of articles in notch signaling in vascular biology across all publications each year (not limited to Nature Index journals).

Technical terms

Notch signalling: A juxtacrine pathway in which cell membrane receptors interact with adjacent cell ligands to control gene expression and cell fate decisions.

Angiogenesis: The formation of new blood vessels from existing vasculature, essential for growth, repair and disease progression.

Endothelial cells (ECs): Cells lining the interior surface of blood vessels, regulating permeability, tone and new vessel formation.

Tip and stalk cells: Specialized endothelial subtypes in sprouting vessels; tip cells lead migration towards angiogenic signals, while stalk cells proliferate to form the vessel lumen.

Vascular remodelling: Structural and functional adaptation of blood vessels in response to mechanical forces, metabolic demands or injury, involving coordinated actions of endothelial and smooth muscle cells.

References

1. Targeting endothelial MYC using siRNA or miR-218 nanoparticles sensitizes chemo- and immuno-therapies by recapitulating the Notch activation-induced tumor vessel normalization. Theranostics (2025).
2. The Notch signaling-regulated angiogenesis in rheumatoid arthritis: pathogenic mechanisms and therapeutic potentials. Frontiers in Immunology (2023).
3. Notch Signaling Regulates Immune Responses in Atherosclerosis. Frontiers in Immunology (2019).
4. Notch Signaling in Endothelial Cells: Is It the Therapeutic Target for Vascular Neointimal Hyperplasia?. International Journal of Molecular Sciences (2017).