Increased Expression of Angiogenic Factors in Human Colonic Angiodysplasia

Junquera, Félix; Saperas, Esteban; Torres, Inés de; Vidal, María; Malagelada, Juan–R.

doi:10.1111/j.1572-0241.1999.01017.x

Cited by 136 publications

(69 citation statements)

References 27 publications

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Section: Introductionmentioning

confidence: 99%

“…Recent studies have suggested that angiogenesis is involved in the pathogenesis of vascular malformations. 21 Increased VEGF expression has been reported in human colonic angiodysplasia 22 and, more recently, anti-angiogenic treatments have been cautiously tested to control bleeding from vascular malformations, with promising results (reviewed by Bauditz and Lochs 23 ).Because of its relationship with regulators of angiogenesis and the clinical observations of angiodysplasia in VWD patients, we postulated that VWF may regulate angiogenesis. Using human umbilical vein ECs (HUVECs), we found that inhibition of VWF expression by short interfering RNA (siRNA) in vitro resulted in increased stability of the capillary network in a 3D tube-formation assay, increased VEGFR-2-dependent proliferation and migration, which was coupled to a decrease in ␣v␤3 levels and activity and increased Ang-2 release.…”

mentioning

confidence: 97%

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Endothelial von Willebrand factor regulates angiogenesis

Starke

Ferraro

Paschalaki

et al. 2011

Blood

426

280

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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...

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Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 97%

Endothelial von Willebrand factor regulates angiogenesis

Starke

Ferraro

Paschalaki

et al. 2011

Blood

426

280

View full text Add to dashboard Cite

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“…VEGF, so far the best characterized angiogenic molecule, stimulates proliferation of vascular endothelial cells and increases vascular permeability, and thus is a central mediator of the early phase of angiogenesis [10] . Recent studies have confirmed that both Osler's disease and nonhereditary intestinal angiodysplasias are characterized by increased production of VEGF [11,12] . High serum levels of VEGF that also correlate with severity of bleeding are found in patients with Osler's disease [11] .…”

Section: Mechanisms Of Bleedingmentioning

confidence: 85%

“…Expression of VEGF receptor 1 is also observed in bleeding intestinal angiodysplasias [12] . As VEGF receptor 1 is specifically up-regulated by hypoxia, this finding may indicate a role for hypoxia in the pathogenesis of angiodysplasias [13,14] .…”

Section: Mechanisms Of Bleedingmentioning

confidence: 92%

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Angiogenesis and vascular malformations: Antiangiogenic drugs for treatment of gastrointestinal bleeding

Juergen¹,

Bauditz²,

Herbert³

et al. 2007

WJG

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Treatment of gastrointestinal bleeding in patients with angiodysplasias and Osler's disease (hereditary hemorrhagic telangiectasia) is clinically challenging. Frequently, vascular malformations occur as multiple disseminated lesions, making local treatment an unfavorable choice or impossible. After local therapy, lesions often recur at other sites of the intestine. However, as there are few therapeutic alternatives, repeated endoscopic coagulations or surgical resections are still performed to prevent recurrent bleeding. Hormonal therapy has been employed for more than 50 years but has recently been shown to be ineffective. Therefore, new therapeutic strategies are required. Understanding of the pathophysiology of angiogenesis and vascular malformations has recently substantially increased. Currently, multiple inhibitors of angiogenesis are under development for treatment of malignant diseases. Experimental and clinical data suggest that antiangiogenic substances, which were originally developed for treatment of malignant diseases, may also represent long-awaited specific drugs for the treatment of vascular malformations. However, antiangiogenics display significantly different actions and side-effects. Although antiangiogenics like thalidomide seem to inhibit gastrointestinal bleeding, other substances like bevacizumab can cause mucosal bleeding. Therefore differential and cautious evaluation of this therapeutic strategy is necessary.

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