In this video lecture, Dr. Anna Randi discusses:
- The role of von Willebrand factor in regulating angiogenesis and maintaining vascular integrity beyond its function in hemostasis.
- How abnormal angiogenesis contributes to gastrointestinal angiodysplasia and bleeding in patients with von Willebrand disease.
- Emerging evidence that targeting angiopoietin-2 may offer a novel therapeutic strategy for vascular complications of VWD.
Anna Randi is Professor of Cardiovascular Medicine at the National Heart and Lung Institute, Imperial College London. Her research interests are in vascular biology and haemostasis. The Randi lab has defined transcriptional and epigenetic mechanisms that control endothelial cell homeostasis and resilience in health and disease and identified of von Willebrand factor as a regulator of angiogenesis. The lab also pioneered the study of circulating endothelial cells from patients’ blood (ECFC) to define disease mechanisms in von Willebrand disease and cardiovascular diseases.
Anna Randi is a clinically qualified haematologist. She studied Medicine at the University of Milan (Italy), and trained at Washington University, St. Louis (USA) and the Imperial Cancer research UK (now Crick). In 2003, she set up her laboratory at Imperial College London where she has been ever since. From 2018 to 2025, she was Head of the Vascular Science Section.
Anna is actively involved in the vascular biology and homeostasis communities and has covered several roles in international organisations (including European Vascular Biology Organisation (EVBO), American Heart Association (AHA) and International Society of Thrombosis and Haemostasis (ISTH). Anna is committed to promoting the careers of young researchers, providing a supportive and stimulating training and working environment, with a particular focus on gender equality.
https://profiles.imperial.ac.uk/a.randi
(Video Lecture Summary)
Introduction
Dr. Anna Randi explores the relationship between von Willebrand factor (VWF) and angiogenesis, highlighting how VWF contributes not only to hemostasis but also to the maintenance of normal blood vessel architecture. She focuses on gastrointestinal angiodysplasia, a major cause of chronic bleeding in patients with von Willebrand disease (VWD), and reviews experimental evidence supporting a direct role for VWF in regulating angiogenesis. The lecture concludes by discussing angiopoietin-2 as a potential therapeutic target for this challenging complication.
Angiogenesis and Vascular Homeostasis
Angiogenesis, the formation of new blood vessels from existing vasculature, is an essential physiologic process involved in development, pregnancy, the menstrual cycle, and wound healing. It also contributes to pathological conditions including cancer, retinal disease, and vascular malformations.
Dr. Randi emphasizes that angiogenesis is highly context dependent. The molecular pathways that regulate blood vessel growth vary according to the tissue, developmental stage, and local environment. Endothelial activation, proliferation, migration, and vessel maturation must be tightly coordinated to produce stable, functional vasculature. Although vascular endothelial growth factor (VEGF) is a central regulator of angiogenesis, numerous additional pathways influence vessel formation, stabilization, and remodeling.
VWF Beyond Hemostasis
VWF is best known for its essential role in primary hemostasis, where it mediates platelet adhesion and serves as the carrier protein for factor VIII. It is synthesized by endothelial cells and megakaryocytes, assembled into high-molecular-weight multimers, and stored within endothelial Weibel-Palade bodies before release into the circulation.
Dr. Randi explains that these endothelial storage organelles are also important because they contain other biologically active proteins involved in vascular regulation. This observation prompted investigators to ask whether VWF itself might influence endothelial biology beyond coagulation.
Gastrointestinal Angiodysplasia in VWD
Gastrointestinal bleeding remains one of the most difficult complications to manage in VWD. It occurs most commonly in patients with severe disease or those who lack high-molecular-weight VWF multimers, including individuals with type 2A, type 3, and acquired von Willebrand syndrome.
The underlying lesion is gastrointestinal angiodysplasia, a vascular malformation composed of fragile, dilated blood vessels that are prone to recurrent bleeding. Although angiodysplasia also occurs in the general population, patients with VWD experience the combined effects of abnormal vasculature and impaired hemostasis, creating a particularly challenging clinical problem. Current replacement therapies often fail to fully control bleeding from these lesions, highlighting the need for new therapeutic approaches.
Evidence That VWF Regulates Angiogenesis
Dr. Randi reviews studies demonstrating that reducing VWF expression in endothelial cells increases angiogenic activity. Experimental knockdown of VWF resulted in increased endothelial migration, proliferation, and angiogenic behavior in multiple in vitro assays. Some of these abnormalities could be partially normalized by inhibiting VEGF receptor 2 signaling, suggesting that VWF normally restrains angiogenic pathways. These findings established VWF as an endogenous modulator of angiogenesis rather than solely a hemostatic protein.
How VWF Influences Angiogenesis
Several mechanisms may explain how VWF regulates blood vessel formation.
At the cell surface, VWF interacts with integrin αVβ3, which influences VEGF receptor 2 signaling. Intracellularly, VWF is required for the formation of Weibel-Palade bodies, where numerous regulatory proteins are stored.
One particularly important cargo protein is angiopoietin-2, a key regulator of endothelial activation and angiogenesis. Under normal conditions, angiopoietin-2 is retained within Weibel-Palade bodies until endothelial activation triggers its release. Dr. Randi hypothesized that absence of VWF disrupts this storage mechanism and alters angiopoietin signaling.
The Angiopoietin-2 Pathway
Angiopoietin-1 and angiopoietin-2 exert opposing effects through the endothelial Tie2 receptor. Angiopoietin-1 promotes vascular stability and suppresses inflammation and permeability. In contrast, angiopoietin-2 competes for Tie2 binding and promotes endothelial activation, inflammation, and angiogenesis.
Studies from Dr. Randi’s laboratory demonstrated that VWF-deficient endothelial cells not only release excess angiopoietin-2 but also produce increased amounts of the protein. This creates an imbalance favoring angiopoietin-2 over angiopoietin-1. Similar alterations were observed in VWF-deficient mice and in patients with angiodysplasia, supporting the clinical relevance of this pathway.
Abnormal Angiogenesis in the Intestine
The intestinal microvasculature represents a unique vascular environment because it is continually exposed to gradients of oxygen, nutrients, microbial products, and inflammatory stimuli. Using VWF-deficient mice, Dr. Randi’s group demonstrated that intestinal blood vessels develop abnormal architecture in the absence of VWF. Rather than forming well-organized vascular channels, the vessels exhibited impaired remodeling, irregular lumen formation, and reduced structural integrity.
These findings support the hypothesis that VWF deficiency results in abnormal rather than simply excessive angiogenesis, providing a mechanistic explanation for gastrointestinal angiodysplasia.
Patient-Derived Endothelial Cell Models
To investigate these mechanisms in humans, Dr. Randi describes the use of endothelial colony-forming cells (ECFCs), which are isolated from peripheral blood and serve as patient-specific endothelial models.
ECFCs from patients with type 3 VWD revealed important differences between individuals with distinct molecular defects. Some patients produced no detectable VWF, while others synthesized intracellular VWF that became trapped within the endoplasmic reticulum and failed to form normal Weibel-Palade bodies.
These cellular phenotypes illustrate how studying endothelial cells can reveal disease mechanisms that are not apparent from plasma laboratory testing alone.
Three-Dimensional Models of Angiogenesis
To better model vascular development, Dr. Randi’s group developed a three-dimensional microfluidic angiogenesis platform using patient-derived ECFCs.
Although VWF-deficient cells initially appeared to generate larger vascular networks, detailed three-dimensional imaging demonstrated that these structures were poorly organized. Endothelial cells struggled to form stable lumens and instead produced disorganized sheets with defective remodeling.
The findings suggest that VWF deficiency causes abnormal angiogenesis characterized by impaired vascular maturation rather than simply increased vessel growth.
Targeting Angiopoietin-2
The mechanistic findings also suggested a potential therapeutic strategy.
Treatment of VWF-deficient endothelial networks with an anti-angiopoietin-2 antibody restored a more normal vascular architecture in vitro. Based on these results, Dr. Randi proposes that inhibition of angiopoietin-2 may eventually become a treatment for gastrointestinal angiodysplasia in VWD.
She notes that additional pathways, including VEGF signaling, integrin αVβ3, and the specific contribution of high-molecular-weight VWF multimers, remain important areas for future investigation.
Broader Implications
Dr. Randi concludes by considering whether vascular abnormalities in VWD extend beyond the gastrointestinal tract.
Although gastrointestinal angiodysplasia is the most common manifestation, vascular abnormalities have also been reported in other organs, particularly among patients with severe disease or loss of high-molecular-weight multimers. She also raises the possibility that abnormal angiogenesis may contribute to heavy menstrual bleeding and postpartum hemorrhage, although direct evidence for uterine vascular abnormalities is currently lacking.
These observations broaden the understanding of VWD from a disorder of coagulation alone to one that also involves blood vessel biology.
Conclusion
Dr. Randi concludes that effective control of bleeding depends on both normal hemostasis and intact vascular integrity. Her work demonstrates that VWF is an important regulator of angiogenesis through its effects on endothelial biology and angiopoietin-2 signaling. These discoveries provide a mechanistic explanation for gastrointestinal angiodysplasia in VWD and identify angiopoietin-2 as a promising therapeutic target for patients whose bleeding cannot be adequately controlled with conventional replacement therapies.