Endothelial von Willebrand factor regulates angiogenesis

Abstract

The regulation of blood vessel formation is of fundamental importance to many physiological processes, and angiogenesis is a major area for novel therapeutic approaches to diseases from ischemia to cancer. A poorly understood clinical manifestation of pathological angiogenesis is angiodysplasia, vascular malformations that cause severe gastrointestinal bleeding. Angiodysplasia can be associated with von Willebrand disease (VWD), the most common bleeding disorder in man. VWD is caused by a defect or deficiency in von Willebrand factor (VWF), a glycoprotein essential for normal hemostasis that is involved in inflammation. We hypothesized that VWF regulates angiogenesis. Inhibition of VWF expression by short interfering RNA (siRNA) in endothelial cells (ECs) caused increased in vitro angiogenesis and increased vascular endothelial growth factor (VEGF) receptor-2 (VEGFR-2)-dependent proliferation and migration, coupled to decreased integrin ␣v␤3 levels and increased angiopoietin (Ang)-2 release. ECs expanded from blood- IntroductionAngiogenesis, the formation of new vessels from pre-existing ones, occurs physiologically in specific circumstances such as wound healing and the menstrual cycle. Dysregulated angiogenesis contributes to the pathogenesis of many disorders, including diabetes, cancer, and macular degeneration (reviewed in Carmeliet 1 ). Angiogenic factors such as vascular endothelial growth factor (VEGF) and the angiopoietins (Ang) orchestrate signaling pathways that promote endothelial cell (EC) migration, proliferation, and ultimately the formation of a new vessel. VEGF-A is a major regulator of angiogenesis (reviewed in Grothey and Galanis 2 ) and acts on ECs mainly through VEGF receptor-2 (VEGFR-2), a tyrosine kinase receptor (reviewed in Olsson 3 ), to promote endothelial proliferation, migration, and sprouting of tip cells in the early stages of angiogenesis (reviewed in Gerhardt 4 ). Ang-1 and Ang-2, which bind to the endothelial Tie-2 receptor, act in the later stages of blood vessel formation and are essential for the maturation of a stable vascular network and for the maintenance of endothelial integrity (reviewed in Thomas and Augustin 5 ). Ang-1 and Ang-2 were originally identified as agonist and antagonist of Tie-2 signaling, respectively, with Ang-1 supporting EC survival and endothelial integrity 6 and Ang-2 promoting blood vessel destabilization and regression. 7 However, recent data suggest a more complex picture that includes cross-talk between the VEGF and the Ang pathways. 8 Growth factor signaling pathways are influenced by surface adhesion molecules that mediate cell-cell or cell-matrix interactions, particularly by members of the integrin superfamily. The integrin that has received most attention in ECs is ␣v␤3 (reviewed in Hodivala-Dilke 9 ), which mediates binding to several extracellular matrix proteins and growth factor receptors including VEGFR-2, thus influencing VEGFR-2 signaling (reviewed in Somanath et al 10 ). ␣v␤3 plays a complex role in angiogenesis. Although the origina...

Prognostic value of preoperative von Willebrand factor plasma levels in patients with Glioblastoma

“…Furthermore, VWF is essential for WPB formation which contain several molecules involved in angiogenesis such as P‐selectin, angiopoietin‐2, and interleukin‐8 26. In addition, VWF is able to control VEGF signaling through multiple mechanisms involving both integrin α v β 3 and angiopoietin 2 27, suggesting a role for VWF in angiogenesis modulation 10. In our study, patients with GBM had higher plasma VWF:Ag levels than those with benign expansive brain lesions.…”

ERG-Mediated Cell Invasion: A Link between Development and Tumorigenesis

“…This study confirmed that ERG drives the basal expression of intracellular adhesion molecule (ICAM)-2, a constitutively expressed cell-cell adhesion molecule in endothelial cells [41]. In addition, this study identified 4 new target genes activated by ERG: von Willebrand Factor (VWF) , which negatively regulates angiogenesis [42]; secreted protein acidic and rich in cysteine (SPARC) , which also negatively regulates angiogenesis [43]; thrombospondin-1 (TSP-1) , another inhibitor of angiogenesis [44], and RhoA , which regulates actin cytoskeleton dynamics [45]. It remains unclear why ERG overexpression has been linked with aggressive prostate cancer; yet these downstream targets of ERG inhibit angiogenesis.…”

von Willebrand Factor: More Than a Regulator of Hemostasis and Thrombosis

“…A regulatory role for endothelial vWF in angiogenesis has been hypothesized based on the fact that vWF is closely related to other well-known regulators of angiogenesis and angiodysplasia in vWD patients [38,39]. To test this hypothesis, Starke et al [40] used short interfering RNA (siRNA) to inhibit vWF expression in HUVECs, and observed stimulated results in angiogenesis, and improved vascular endothelial growth factor (VEGF) receptor-2 (VEGFR-2)-dependent proliferation and migration. VEGFR2 is an important receptor for the key angiogenesis-mediator hormone VEGF-A.…”