BackgroundAn increased incidence of venous thromboembolism (VTE) is associated with anti-vascular endothelial growth factor (VEGF) treatment in cancer. However, the mechanism underlying this effect remains elusive. In this study, we examined the effect of bevacizumab, a humanized monoclonal antibody against VEGF-A, on VTE in a murine xenograft A549 cell tumor model.MethodsInferior vena cava stenosis model and FeCl3-induced saphenous vein thrombosis model were performed in a mouse xenograft models of human lung adenocarcinoma.ResultsWe found that treatment with bevacizumab significantly increased the thrombotic response to inferior vena cava obstruction and femoral vein injury. Plasminogen activator inhibitor (PAI-1) expression in tumors, plasma, and thrombi was significantly increased by bevacizumab. However, bevacizumab did not enhance VTE in PAI-1-deficient mice, suggesting that PAI-1 is a major mediator of bevacizumab’s prothrombotic effect. VEGF inhibited expression of PAI-1 by A549 cells, and this effect was neutralized by bevacizumab, suggesting that bevacizumab increases PAI-1 expression in vivo by blocking the inhibitory effect of VEGF on PAI-1 expression by tumor cells. Pharmacological inhibition of PAI-1 with PAI-039 blocked bevacizumab-induced venous thrombosis.ConclusionCollectively, these findings indicate that PAI-1 plays a role in VTE associated with antiangiogenic therapy and the inhibition of PAI-1 shows efficacy as a therapeutic strategy for the prevention of bevacizumab-associated VTE.

Glycation of vessel wall proteins is thought to have an important role in the pathogenesis of vascular complications in diabetes mellitus. However, no previous study has implicated glycated vitronectin (VN) in the control of vascular endothelial growth factor (VEGF) signaling. To explore whether the glycation of VN affects angiogenic signaling and to understand the molecular mechanisms involved, we synthesized glycated VN by incubating VN with methylglyoxal (MGO) in vitro and identified the formation of glycated VN by an LC–ESI–MS/MS-based method. We tested the hypothesis that glycation of VN downregulates VEGF receptor-2 (VEGFR-2) activation by uncoupling the interaction between VEGFR-2 and αvβ3. Unmodified and MGO-glycated VN were used as substrates for human umbilical vein endothelial cells (HUVECs). The effects of glycated VN on VEGF signaling in HUVECs were investigated. The glycation of VN inhibited VEGF-induced phosphorylation of VEGFR-2 and the intracellular signaling pathway downstream of VEGFR-2. Glycated VN inhibited the binding of VEGFR-2 to β3 integrin and inhibited the phosphorylation of β3 integrin. Furthermore, glycation of VN significantly decreased VEGF-induced migration of HUVECs in vitro and vessel outgrowth in an ex vivo angiogenesis model. Collectively, these data indicate that the glycation of VN inhibits VEGF-induced VEGFR-2 activation by uncoupling VEGFR-2–αvβ3 integrin cross-talk. The glycation of VN causes a reduction in the migration of endothelial cells and vessel outgrowth. This may provide a mechanism for the failure of collateral sprouting in diabetic microangiopathy.

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Background: The flowers of Carthamus tinctorius L. are widely used in traditional Chinese medicine to treat cerebrovascular and cardiovascular diseases. Hydroxysafflor yellow A (HSYA), the main constituent of C. tinctorius L. flowers, is known for its multiple biological activities. The present study investigated the effects of HSYA on angiogenesis in vitro and in a mouse hindlimb ischemia model. Methods: Using human umbilical vein endothelial cells (HUVEC) in vitro and a mouse hindlimb ischemia model in vivo, the angiogenic role of HSYA was evaluated. Results: HSYA significantly increased the capillary-like tube formation and migration of HUVEC. HSYA not only induced a rise in the expression of angiopoietin 1 and Tie-2 but it also increased phosphorylation of Tie-2, Akt, and extracellular signal-regulated kinase 1/2. Furthermore, an anti-Tie-2 neutralizing antibody significantly inhibited HSYA-induced HUVEC tube formation and migration. In vivo, the recovery of perfusion of ischemic hindlimb tissue after femoral artery interruption was significantly increased in HSYA-treated mice compared to vehicle controls. Consistent with these results, the arteriole and capillary densities in ischemic gastrocnemius muscles were significantly increased in HSYA-treated mice. Conclusions: These results indicate the potential utility of HSYA for the treatment of ischemic diseases.

These findings suggest that platelet-derived FV contributes to the control of angiogenesis and is likely associated with thrombin generation.