Angiogenic Factors
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2021 ◽  
Vol 14 (1) ◽  
Jin-Woo Lee ◽  
Jin Hur ◽  
Yoo-Wook Kwon ◽  
Cheong-Whan Chae ◽  
Jae-Il Choi ◽  

Abstract Background Little is known about endogenous inhibitors of angiogenic growth factors. In this study, we identified a novel endogenous anti-angiogenic factor expressed in pericytes and clarified its underlying mechanism and clinical significance. Methods Herein, we found Kai1 knockout mice showed significantly enhanced angiogenesis. Then, we investigated the anti-angiogenic roll of Kai1 in vitro and in vivo. Results KAI1 was mainly expressed in pericytes rather than in endothelial cells. It localized at the membrane surface after palmitoylation by zDHHC4 enzyme and induced LIF through the Src/p53 pathway. LIF released from pericytes in turn suppressed angiogenic factors in endothelial cells as well as in pericytes themselves, leading to inhibition of angiogenesis. Interestingly, KAI1 had another mechanism to inhibit angiogenesis: It directly bound to VEGF and PDGF and inhibited activation of their receptors. In the two different in vivo cancer models, KAI1 supplementation significantly inhibited tumor angiogenesis and growth. A peptide derived from the large extracellular loop of KAI1 has been shown to have anti-angiogenic effects to block the progression of breast cancer and retinal neovascularization in vivo. Conclusions KAI1 from PC is a novel molecular regulator that counterbalances the effect of angiogenic factors.

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Youfeng Li ◽  
Yuning Zhang ◽  
Hua Wang ◽  
Chengfeng Sun ◽  
Dongmei Liu ◽  

Critical limb ischemia (CLI), an end-stage manifestation of peripheral artery disease (PAD), still lacks effective therapeutic strategies. Recently, dental pulp-derived mesenchymal stem cells (DP-MSCs) have been attracting more and more attentions in therapeutic applications due to their high proliferation ability, powerful osteogenic differentiation potential, and effective anti-inflammatory effects. In this study, we compared the therapeutic effects of MSCs derived from different sources in a femoral artery-ligated preclinical ischemic model. We found that treatments with MSCs, including bone marrow- (BM-), adipose- (AD-), dental pulp- (DP-), and umbilical cord- (UC-) derived MSCs, improved limb functions, reduced inflammatory responses, increased angiogenesis, and promoted regeneration of muscle fiber. Among them, DP-MSCs and BM-MSCs produced much more impressive effects in restoring limb functions and promoting angiogenesis. The flow velocity restored to nearly 20% of the normal level at 3 weeks after treatments with DP-MSCs and BM-MSCs, and obvious capillary proliferation and collateral development could be observed. Although neovascularization was induced in the ischemic limb after ligation, MSCs, especially DP-MSCs, significantly enhanced the angiogenesis. In vitro experiments showed that serum deprivation improved the expression of angiogenic factors, growth factors, and chemokines in DP-MSCs and UC-MSCs, but not in BM-MSCs and AD-MSCs. However, DP-MSCs produced stronger therapeutic responses than UC-MSCs, which might be due to the higher expression of hepatocyte growth factor (HGF) and hypoxia-inducible factor-1 α (HIF-1α). We speculated that DP-MSCs might stimulate angiogenesis and promote tissue repair via expressing and secreting angiogenic factors, growth factors, and chemokines, especially HGF and HIF-1α. In conclusion, DP-MSCs might be a promising approach for treating CLI.

2021 ◽  
Vol 2021 ◽  
pp. 1-18
Mingzhu Yang ◽  
Ruiqi Qiu ◽  
Weiping Wang ◽  
Jingyang Liu ◽  
Xiuxiu Jin ◽  

Age-related macular degeneration (AMD) is a common and severe blinding disease among people worldwide. Retinal inflammation and neovascularization are two fundamental pathological processes in AMD. Recent studies showed that P2X7 receptor was closely involved in the inflammatory response. Here, we aim to investigate whether A740003, a P2X7 receptor antagonist, could prevent retinal inflammation and neovascularization induced by oxidized low-density lipoprotein (ox-LDL) and explore the underlying mechanisms. ARPE-19 cells and C57BL/6 mice were treated with ox-LDL and A740003 successively for in vitro and in vivo studies. In this research, we found that A740003 suppressed reactive oxygen species (ROS) generation and inhibited the activation of Nod-like receptor pyrin-domain protein 3 (NLRP3) inflammasome and nuclear factor-κB (NF-κB) pathway. A740003 also inhibited the generation of angiogenic factors in ARPE-19 cells and angiogenesis in mice. The inflammatory cytokines and phosphorylation of inhibitor of nuclear factor-κB alpha (IKBα) were repressed by A740003. Besides, ERG assessment showed that retinal functions were remarkably preserved in A740003-treated mice. In summary, our results revealed that the P2X7 receptor antagonist reduced retinal inflammation and neovascularization and protected retinal function. The protective effects were associated with regulation of NLRP3 inflammasome and the NF-κB pathway, as well as inhibition of angiogenic factors.

2021 ◽  
Vol 13 ◽  
Erik B. Erhardt ◽  
John C. Adair ◽  
Janice E. Knoefel ◽  
Arvind Caprihan ◽  
Jillian Prestopnik ◽  

Dual pathology of Alzheimer's disease (AD) and vascular cognitive impairment and dementia (VCID) commonly are found together at autopsy, but mixed dementia (MX) is difficult to diagnose during life. Biological criteria to diagnose AD have been defined, but are not available for vascular disease. We used the biological criteria for AD and white matter injury based on MRI to diagnose MX. Then we measured multiple biomarkers in CSF and blood with multiplex biomarker kits for proteases, angiogenic factors, and cytokines to explore pathophysiology in each group. Finally, we used machine learning with the Random forest algorithm to select the biomarkers of maximal importance; that analysis identified three proteases, matrix metalloproteinase-10 (MMP-10), MMP-3 and MMP-1; three angiogenic factors, VEGF-C, Tie-2 and PLGF, and three cytokines interleukin-2 (IL-2), IL-6, IL-13. To confirm the clinical importance of the variables, we showed that they correlated with results of neuropsychological testing.

BMJ Open ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. e046161
Jing Zhu ◽  
Jun Zhang ◽  
Nurul Syaza Razali ◽  
Bernard Chern ◽  
Kok Hian Tan

ObjectivePrevious studies suggested mean arterial pressure (MAP) had moderate predictive values in the first and second trimesters for the prediction of preeclampsia. However, the performance of MAP in Asian women is still unclear. The objective of this study was to examine the predictive values of MAP in Asian population throughout gestation, and to compare the performance of MAP, angiogenic factors and uterine artery Doppler in the prediction of preeclampsia.DesignA prospective cohort study.SettingKK Women’s and Children’s Hospital, Singapore.ParticipantsA total of 926 women with singleton pregnancy less than 14 weeks of gestation were included in the prospective Neonatal and Obstetrics Risks Assessment cohort between September 2010 and October 2014. Maternal blood pressure levels, uterine artery pulsatility index (UtA-PI), serum soluble fms-like tyrosine kinase 1 (sFlt-1), placental growth factor (PlGF) and sFlt-1/PlGF ratio were measured at 11–14, 18–22, 28–32 and 34 weeks onward, respectively.Primary and secondary outcomesPreeclampsia was the main pregnancy outcome.ResultsA total of 20 women developed preeclampsia, who had significantly lower levels of PlGF, higher levels of sFlt-1/PlGF ratio and MAP throughout pregnancy than women without preeclampsia. Compared with angiogenic factors and UtA-PI, MAP had significantly higher area under the receiver operating characteristic curves (AUCs) for predicting preeclampsia and term preeclampsia throughout gestation. For predicting preeclampsia, MAP had AUCs of 0.86 (95% CI 0.78 to 0.95), 0.87 (95% CI 0.80 to 0.95) and 0.91 (95% CI 0.85 to 0.98) at 11–14, 18–22 and 28–32 weeks, respectively. For predicting term preeclampsia, MAP yielded AUCs of 0.87 (95% CI 0.75 to 0.99), 0.87 (95% CI 0.76 to 0.98) and 0.90 (95% CI 0.80 to 0.99) at 11–14, 18–22 and 28–32 weeks, respectively. For predicting preterm preeclampsia, the performance of MAP and PlGF was similar.ConclusionMAP is a good predictor for preeclampsia, especially term preeclampsia, in Asian women.

2021 ◽  
Vol 10 (15) ◽  
pp. 3384
Natalie K. Binder ◽  
Teresa M. MacDonald ◽  
Sally A. Beard ◽  
Natasha de Alwis ◽  
Stephen Tong ◽  

Despite significant maternal and fetal morbidity, a treatment for preeclampsia currently remains an unmet need in clinical care. As too does the lifelong cardiovascular risks imparted on preeclampsia sufferers. Endothelial dysfunction and end-organ injury are synonymous with both preeclampsia and cardiovascular disease, including heart failure. We propose that beta-blockers, known to improve endothelial dysfunction in the treatment of cardiovascular disease, and specifically known to reduce mortality in the treatment of heart failure, may be beneficial in the treatment of preeclampsia. Here, we assessed whether the beta-blockers carvedilol, bisoprolol, and metoprolol could quench the release of anti-angiogenic factors, promote production of pro-angiogenic factors, reduce markers of inflammation, and reduce endothelial dysfunction using our in vitro pre-clinical preeclampsia models encompassing primary placental tissue and endothelial cells. Here, we show beta-blockers effected a modest reduction in secretion of anti-angiogenic soluble fms-like tyrosine kinase-1 and soluble endoglin and increased expression of pro-angiogenic placental growth factor, vascular endothelial growth factor and adrenomedullin in endothelial cells. Beta-blocker treatment mitigated inflammatory changes occurring after endothelial dysfunction and promoted cytoprotective antioxidant heme oxygenase-1. The positive effects of the beta-blockers were predominantly seen in endothelial cells, with a less consistent response seen in placental cells/tissue. In conclusion, beta-blockers show potential as a novel therapeutic approach in the treatment of preeclampsia and warrant further investigation.

2021 ◽  
Vol 21 (1) ◽  
Megan E. Smithmyer ◽  
Chileshe M. Mabula-Bwalya ◽  
Humphrey Mwape ◽  
Gabriel Chipili ◽  
Bridget M. Spelke ◽  

Abstract Background Maternal HIV increases the risk of adverse birth outcomes including preterm birth, fetal growth restriction, and stillbirth, but the biological mechanism(s) underlying this increased risk are not well understood. We hypothesized that maternal HIV may lead to adverse birth outcomes through an imbalance in angiogenic factors involved in the vascular endothelial growth factor (VEGF) signaling pathway. Methods In a case–control study nested within an ongoing cohort in Zambia, our primary outcomes were serum concentrations of VEGF-A, soluble endoglin (sEng), placental growth factor (PlGF), and soluble fms-like tyrosine kinase-1 (sFLT-1). These were measured in 57 women with HIV (cases) and 57 women without HIV (controls) before 16 gestational weeks. We used the Wilcoxon rank-sum and linear regression controlling for maternal body mass index (BMI) and parity to assess the difference in biomarker concentrations between cases and controls. We also used logistic regression to test for associations between biomarker concentration and adverse pregnancy outcomes (preeclampsia, preterm birth, small for gestational age, stillbirth, and a composite of preterm birth or stillbirth). Results Compared to controls, women with HIV had significantly lower median concentrations of PlGF (7.6 vs 10.2 pg/mL, p = 0.02) and sFLT-1 (1647.9 vs 2055.6 pg/mL, p = 0.04), but these findings were not confirmed in adjusted analysis. PlGF concentration was lower among women who delivered preterm compared to those who delivered at term (6.7 vs 9.6 pg/mL, p = 0.03) and among those who experienced the composite adverse birth outcome (6.2 vs 9.8 pg/mL, p = 0.02). Median sFLT-1 concentration was lower among participants with the composite outcome (1621.0 vs 1945.9 pg/mL, p = 0.04), but the association was not significant in adjusted analysis. sEng was not associated with either adverse birth outcomes or HIV. VEGF-A was undetectable by Luminex in all specimens. Conclusions We present preliminary findings that HIV is associated with a shift in the VEGF signaling pathway in early pregnancy, although adjusted analyses were inconclusive. We confirm an association between angiogenic biomarkers and adverse birth outcomes in our population. Larger studies are needed to further elucidate the role of HIV on placental angiogenesis and adverse birth outcomes.

2021 ◽  
Yiqun He ◽  
Hailong Li ◽  
Zuochong Yu ◽  
Linli Li ◽  
Xujun Chen ◽  

Abstract Background: Angiogenesis is essential for the tissue engineering bone formation, and osteoblasts (OBs) has been proved to play an important role in angiogenesis via various pro-angiogenic factors. However, whether the mineralized osteoblast derived exosomes (MOB-Exos) and containing let-7f-5p can promote the angiogenesis of endothelial cells (ECs) is still unknown.Methods: MOB-Exos, let-7f-5p mimicked MOB-Exos (miR mimic group) and let-7f-5p inhibited MOB-Exos (miR inhibitor group) were respectively harvested from mineralized osteoblasts (MOBs) and then co-cultured with bEnd.3. Besides, the Erk1/2 signaling pathway in ECs in miR mimic group was inhibited. Subsequently, CCK-8 assays, wound healing assays, transwell migration assays and tube formation assays were performed to detect the angiogenic capability of ECs. Dual luciferase reporter assays were conducted to verify the target genes of exosomal let-7f-5p. Results: The results showed that MOB-Exos could significantly promote the angiogenesis of ECs, which could be enhanced by mimicking exosomal let-7f-5p, and attenuated by inhibiting exosomal let-7f-5p. And the angiogenic capability of ECs was partly impaired after inhibiting the Erk1/2 signaling pathway despite co-cultured with let-7f-5p mimicked MOB-Exos. Moreover, let-7f-5p suppressed the luciferase activity of wide-type DUSP1, while mutation of DUSP1 abrogated the repressive ability of let-7f-5p. Conclusion: Based the results, our study concluded that exosomal let-7f-5p derived from MOBs could promote the angiogenesis of ECs via activating DUSP1/Erk1/2 signaling pathway, which might be a promising target for tissue engineering bone formation.

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