von Willebrand factor regulation of blood vessel formation

Abstract

Several important physiological processes, from permeability to inflammation to hemostasis, take place at the vessel wall and are regulated by endothelial cells (ECs). Thus, proteins that have been identified as regulators of one process are increasingly found to be involved in other vascular functions. Such is the case for von Willebrand factor (VWF), a large glycoprotein best known for its critical role in hemostasis. In vitro and in vivo studies have shown that lack of VWF causes enhanced vascularization, both constitutively and following ischemia. This evidence is supported by studies on blood outgrowth EC (BOEC) from patients with lack of VWF synthesis (type 3 von Willebrand disease [VWD]). The molecular pathways are likely to involve VWF binding partners, such as integrin αvβ3, and components of Weibel-Palade bodies, such as angiopoietin-2 and galectin-3, whose storage is regulated by VWF; these converge on the master regulator of angiogenesis and endothelial homeostasis, vascular endothelial growth factor signaling. Recent studies suggest that the roles of VWF may be tissue specific. The ability of VWF to regulate angiogenesis has clinical implications for a subset of VWD patients with severe, intractable gastrointestinal bleeding resulting from vascular malformations. In this article, we review the evidence showing that VWF is involved in blood vessel formation, discuss the role of VWF high-molecular-weight multimers in regulating angiogenesis, and review the value of studies on BOEC in developing a precision medicine approach to validate novel treatments for angiodysplasia in congenital VWD and acquired von Willebrand syndrome.

Alternative trafficking of Weibel‐Palade body proteins in CRISPR/Cas9‐engineered von Willebrand factor–deficient blood outgrowth endothelial cells

“…However, whereas the punctae of IL‐6 and IL‐8 were diffusely distributed throughout the cell, Ang‐2 shows enrichment at cell‐cell junctions (Figure see also Figure S5). It has been suggested previously that altered angiogenic properties of ECs lacking VWF may be caused by increased constitutive release of Ang‐2, which would then lead to autocrine/paracrine regulation of Tie‐2 signaling . In line with this, we observed that Ang‐2, which in CTRL cells primarily localizes to WPBs and shows minimal overlap with Tie‐2, is primarily found on Tie‐2 positive structures that are enriched at cell‐cell junctions of VWF −/− cells (Figure S5).…”

“…It has been suggested previously that altered angiogenic properties of ECs lacking VWF may be caused by increased constitutive release of Ang-2, which would then lead to autocrine/paracrine regulation of Tie-2 signaling. 28 In line with this, we observed that Ang-2, which in CTRL cells primarily localizes to WPBs and shows minimal overlap with Tie-2, is primarily found on Tie-2 positive structures that are enriched at cell-cell junctions of VWF −/− cells ( Figure S5). This suggests that in the absence of its storage compartment, constitutively released Ang-2 associates with Tie-2 on the plasma membrane.…”

“…WPBs also facilitate the long‐term storage of the angiogenesis mediator Ang‐2 and ensure its on‐demand availability during proangiogenic conditions, for instance, in response to triggering of WPB release by VEGF . Previous studies have also shown altered levels of continuous Ang‐2 release from ECs from patients with VWD or after small interfering RNA–mediated VWF knockdown, which has been suggested to be in part the underlying cause of altered angiogenic properties of VWD patient–derived BOECs and the angiodysplasia that is observed in some patients with VWD .…”

“…In addition, storage and secretion of another WPB cargo protein, the proangiogenic mediator angiopoietin (Ang)‐2 is also disturbed when ECs are depleted of VWF . Continuous release of Ang‐2 as a consequence of the unavailability of its default storage compartment has been proposed as one of the underlying mechanisms behind angiodysplasia, a clinical complication of VWD that is characterized by recurrent bleeding in the gastrointestinal tract and is associated with vascular malformations of the gut . However, studies into angiogenic properties of blood outgrowth endothelial cells (BOECs) derived from patients with VWD, which can be regarded as endothelial models of VWD, have failed to unequivocally support this model …”

“…26 Continuous release of Ang-2 as a consequence of the unavailability of its default storage compartment has been proposed as one of the underlying mechanisms behind angiodysplasia, a clinical complication of VWD that is characterized by recurrent bleeding in the gastrointestinal tract and is associated with vascular malformations of the gut. 27,28 However, studies into angiogenic properties of blood outgrowth endothelial cells (BOECs) derived from patients with VWD, which can be regarded as endothelial models of VWD, have failed to unequivocally support this model. 7,26,29,30 Variation in the genetic background between patients as well as controls may be at the basis of the discrepancy between outcomes in BOECs derived from different individuals.…”