Platelet-derived factor V promotes angiogenesis in a mouse hind limb ischemia model.

OBJECTIVE: Coagulation factor V (FV) is distributed in plasma and platelet pools, which are distinguished by physical and functional differences. FV has been extensively studied for its roles in coagulation. The roles of FV in other physiologic pathways remain understudied. METHODS: Hind limb ischemia was produced in transgenic mice by femoral artery ligation, with different levels of FV gene expression restricted to the plasma or platelets. RESULTS: Hind limb blood flow perfusion in mice with higher platelet FV was significantly increased. The expression of major angiogenesis-related factors was correlated with the level of FV during ischemia. Furthermore, a platelet depletion and transfusion procedure showed that the transfusion of platelets with higher levels of FV into transgenic mice with undetectable platelet FV significantly rescued the ischemia-mediated impairments in blood flow perfusion. Immunohistochemistry analysis also indicated markedly increased capillary formation in the ischemic muscle of mice with higher platelet FV. Moreover, thrombin activity was significantly higher in the mice with higher platelet FV. Platelets expressing higher levels of FV stimulated increased endothelial cell migration. Hind limb blood flow perfusion was significantly blocked by thrombin inhibitor. CONCLUSIONS: These findings suggest that platelet-derived FV contributes to the control of angiogenesis and is likely associated with thrombin generation.

Hydroxysafflor Yellow A Promotes Angiogenesis via the Angiopoietin 1/ Tie-2 Signaling Pathway.

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.

Anti-vascular endothelial growth factor treatment induces blood flow recovery through vascular remodeling in high-fat diet induced diabetic mice.

Diabetes mellitus (DM) leads to the development of microvascular diseases and is associated with impaired angiogenesis. The presence of vascular endothelial growth factor (VEGF) can block PDGF-BB dependent regulation of neovascularization and vessel normalization. We tested the hypothesis that the inhibition of VEGF improves blood flow in a mouse hindlimb ischemia model produced by femoral artery ligation. In this study, we examined the effect of bevacizumab, a humanized monoclonal antibody against VEGF-A, on blood perfusion and angiogenesis after hindlimb ischemia. We showed that bevacizumab induces functional blood flow in high fat chow (HFC)-fed diabetic mice. Treatment with bevacizumab increased the expression of platelet derived growth factor-BB (PDGF-BB) in ischemic muscle, and led to vascular normalization. It also blocked vascular leakage by improving the recruitment of pericytes associated with nascent blood vessels, but it did not affect capillary formation. Furthermore, treatment with an anti-PDGF drug significantly inhibited blood flow perfusion in diabetic mice treated with bevacizumab. These results indicate that bevacizumab improves blood flow recovery through the induction of PDGF-BB in a diabetic mouse hindlimb ischemia model, and that vessel normalization may represent a useful strategy for the prevention and treatment of diabetic peripheral arterial disease.

Bevacizumab promotes venous thromboembolism through the induction of PAI-1 in a mouse xenograft model of human lung carcinoma.

BACKGROUND: An 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. METHODS: Inferior vena cava stenosis model and FeCl3-induced saphenous vein thrombosis model were performed in a mouse xenograft models of human lung adenocarcinoma. RESULTS: We 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. CONCLUSION: Collectively, 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.

The prognostic role of the preoperative platelet to lymphocyte ratio in laryngeal cancer.

Background: In recent years, several studies have investigated the relationship between platelet to lymphocyte ratio (PLR) and the prognosis of patients with laryngeal cancer, but the results remain controversial. This study aimed to evaluate the prognostic significance of pretreatment PLR in patients with laryngeal cancer. Methods: Up to July 2023, we searched PubMed, PubMed Central, Web of Science, Embase, CNKI and Wanfang databases to collect relevant articles evaluating the relationship between PLR and the prognosis of laryngeal cancer. The pooled hazard ratio (HR) and 95% confidence interval (CI) were calculated using the random effect-model. Results: A total of 14 included studies involving 3220 patients with laryngeal cancer were included. The combined results suggested that elevated PLR was associated with poorer overall survival (HR = 2.21, 95% CI, 1.67 - 2.93, p < 0.001), progression-free survival (HR = 2.54, 95% CI, 1.76-3.66, p < 0.001), recurrence-free survival (HR = 1.87, 95% CI,1.45 - 2.42, p < 0.001), and disease-free survival (HR = 1.46, 95% CI, 1.08-1.98, p < 0.001). Subgroup analysis further confirmed that pretreatment PLR was an independent predictor of OS in laryngeal cancer patients. Conclusion: Higher pretreatment PLR is strongly related to poor prognosis of laryngeal cancer patients. This indicates that PLR has the potential to serve as a valuable biomarker for predicting the prognosis of laryngeal cancer. However, further validations in large prospective cohorts are necessary to confirm its clinical utility and reliability.

Antagonizing αvß3 Integrin Improves Ischemia-Mediated Vascular Normalization and Blood Perfusion by Altering Macrophages.

Background: αVß3 integrin has been implicated in the physiological processes and pathophysiology of important angiogenesis-related disorders; however, the preclinical and clinical data on integrin αVß3 antagonists have not demonstrated improved outcomes. Our goal was to test the hypothesis that inhibition of αVß3 integrin improves blood flow in a mouse hindlimb ischemia model. Methods: In this study, we examined the effect of cilengitide, an αVß3/αVß5 integrin-specific RGD-mimetic cyclic peptide, on blood perfusion and angiogenesis after hindlimb ischemia. Blood flow was measured using Laser Doppler Scanner. Vascular density, and macrophages infiltration were examined by immunofluorescence. Macrophage polarization was measured by quantitative real time PCR. Results: We found that low-dose, not high-dose, cilengitide increased blood flow perfusion, capillary formation, and pericyte coverage, accompanied by an accumulation of macrophages and increased expression of the chemokine (C-C motif) ligand 2 (CCL2) in ischemic muscles. Macrophage depletion using clodronate liposomes resulted in a reduction in low-dose cilengitide-induced blood flow perfusion, macrophage accumulation, pericyte coverage, and CCL2 expression. Finally, in vitro assays showed that low-dose, not high-dose, cilengitide increased macrophage migration. Conclusion: These studies identified a novel role of the inhibition of αVß3 integrin in modulating ischemia-induced angiogenesis, possibly through effects on macrophage infiltration and polarization, and revealed αVß3 integrin inhibition to be a promising therapeutic strategy for peripheral artery disease.

Prevalence of Depression among Chinese University Students: A Meta-Analysis.

BACKGROUND: Depression is a major mental health issue worldwide, and university students with heavy burdens of study are at a high risk for depression. While a number of studies have been conducted regarding depression among university students in China, there is a lack of information regarding the national prevalence of depression among Chinese university students. Therefore, we performed a meta-analysis to statistically pool the prevalence of depression among Chinese university students. METHODS: A systematic search of scientific databases was conducted, including Chinese Web of Knowledge, Embase, PubMed, Wanfang (a Chinese database) and Weipu (a Chinese database) to find relevant publications published between 1995 and December 2015. This was supplemented by a secondary review of the reference lists of all retrieved papers to find additional relevant citations. Studies published in either English or Chinese that provided prevalence estimates of depression in Chinese university students were considered. Prevalence estimates of each eligible study were extracted and pooled in our meta-analysis using a random-effects model. RESULTS: A total of 39 studies conducted between 1997 and 2015 including 32,694 university students were analyzed. Our results indicate that the overall prevalence of depression among Chinese university students is 23.8% (95% CI: 19.9%-28.5%). Substantial heterogeneity in prevalence estimates was noted. Subgroup analysis revealed that the prevalence of depression among medical students is higher than among other students. CONCLUSIONS: Overall, the prevalence of depression among Chinese university students is exceedingly high. This suggests that it is imperative that more attention be given to the development of appropriate mental healthcare strategies for university students in China.