VEGF to CITED2 ratio predicts the collateral circulation of acute ischemic stroke

Minyi Lu, Yuben Liu, Zhiqiang Xian, Xiaoyao Yu, Jian Chen, Sheng Tan, Peidong Zhang, Yang Guo, Minyi Lu, Yuben Liu, Zhiqiang Xian, Xiaoyao Yu, Jian Chen, Sheng Tan, Peidong Zhang, Yang Guo

Abstract

Objective: The research objective was to evaluate the predicting role of the vascular endothelial growth factor to CBP/P300-interacting transactivator with Glu/Asp-rich C-terminal domain 2 Ratio (VEGF/CITED2) from peripheral blood mononuclear cells (PBMCs) in the collateral circulation of acute ischemic stroke (AIS).

Methods: In an observational study of patients with AIS, the western blot was applied to test the protein expression of VEGF and CITED2. Then, we calculated the VEGF/CITED2 and collected other clinical data. Binary logistic regression analysis between collateral circulation and clinical data was performed. Finally, receiver operating characteristic (ROC) curve analysis was used to explore the predictive value of VEGF/CITED2.

Results: A total of 67 patients with AIS were included in the study. Binary logistic regression analysis indicated the VEGF/CITED2 (OR 165.79, 95%CI 7.25-3,791.54, P = 0.001) was an independent protective factor. The ROC analyses showed an area under the ROC curve of the VEGF/CITED2 was 0.861 (95%CI 0.761-0.961). The optimal cutoff value of 1.013 for VEGF/CITED2 had a sensitivity of 89.1% and a specificity of 85.7%.

Conclusion: In patients with AIS, the VEGF/CITED2 was related to the establishment of collateral circulation. The VEGF/CITED2 is a potentially valuable biomarker for predicting collateral circulation.

Clinical trial registration: ClinicalTrials.gov, identifier: NCT05345366.

Keywords: AIS; PBMCs; VEGF/CITED2; biomarker; collateral circulation.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Lu, Liu, Xian, Yu, Chen, Tan, Zhang and Guo.

Figures

Figure 1
Figure 1
Schedule of enrollment and assessments. DWI-ASPECTS, diffusion weight image–Alberta Stroke Program Early CT Score; CITED2, CBP/P300-interacting transactivator with Glu/Asp-rich C-terminal domain 2; VEGF, vascular endothelial growth factor; WB, Western blot; NIHSS, National Institute of Health Stroke Scale; MBI, Modified Barthel Index; mRS, Modified Rankin Scale.
Figure 2
Figure 2
Patient selection. DWI-ASPECTS, diffusion weight image–Alberta Stroke Program Early CT Score; CITED2, CBP/P300-interacting transactivator with Glu/Asp-rich C-terminal domain 2; VEGF, vascular endothelial growth factor; WB, Western blot.
Figure 3
Figure 3
Protein expression of CITED2 and VEGF.
Figure 4
Figure 4
ROC curve analysis of the VEGF/CITED2 in the collateral circulation of AIS.

References

    1. Feigin VL, Forouzanfar MH, Krishnamurthi R, Mensah GA, Connor M, Bennett DA, et al. . Global and regional burden of stroke during 1990-2010: findings from the global burden of disease study 2010. Lancet. (2014) 383:245–54. 10.1016/S0140-6736(13)61953-4
    1. Brozici M, van der Zwan A, Hillen B. Anatomy and functionality of leptomeningeal anastomoses: a review. Stroke. (2003) 34:2750–62. 10.1161/01.STR.0000095791.85737.65
    1. Soares BP, Tong E, Hom J, Cheng SC, Bredno J, Boussel L, et al. . Reperfusion is a more accurate predictor of follow-up infarct volume than recanalization: a proof of concept using CT in acute ischemic stroke patients. Stroke. (2010) 41:e34–40. 10.1161/STROKEAHA.109.568766
    1. Liebeskind DS, Cotsonis GA, Saver JL, Lynn MJ, Turan TN, Cloft HJ, et al. . Collaterals dramatically alter stroke risk in intracranial atherosclerosis. Ann Neurol. (2011) 69:963–74. 10.1002/ana.22354
    1. Liu L, Ding J, Leng X, Pu Y, Huang LA, Xu A„ et al. Guidelines for evaluation and management of cerebral collateral circulation in ischemic stroke 2017. Stroke Vasc Neurol. (2018) 3:117–30. 10.1136/svn-2017-000135
    1. Resnick N, Yahav H, Khachigian LM, Collins T, Anderson KR, Dewey FC, et al. . Endothelial gene regulation by laminar shear stress. Adv Exp Med Biol. (1997) 430:155–64. 10.1007/978-1-4615-5959-7_13
    1. Iba O, Matsubara H, Nozawa Y, Fujiyama S, Amano K, Mori Y, et al. . Angiogenesis by implantation of peripheral blood mononuclear cells and platelets into ischemic limbs. Circulation. (2002) 106:2019–25. 10.1161/01.cir.0000031332.45480.79
    1. Gorenjak V, Vance DR, Petrelis AM, Stathopoulou MG, Dadé S, El Shamieh S, et al. . Peripheral blood mononuclear cells extracts VEGF protein levels and VEGF mRNA: associations with inflammatory molecules in a healthy population. PLoS ONE. (2019) 14:e220902. 10.1371/journal.pone.0220902
    1. Sun P, Zhang K, Hassan SH, Zhang X, Tang X, Pu H, et al. . Endothelium-targeted deletion of microRNA-15a/16-1 promotes poststroke angiogenesis and improves long-term neurological recovery. Circ Res. (2020) 126:1040–57. 10.1161/CIRCRESAHA.119.315886
    1. Clayton JA, Chalothorn D, Faber JE. Vascular endothelial growth factor-A specifies formation of native collaterals and regulates collateral growth in ischemia. Circ Res. (2008) 103:1027–36. 10.1161/CIRCRESAHA.108.181115
    1. Bhattacharya S, Michels CL, Leung MK, et al. . Functional role of p35srj, a novel p300/CBP binding protein, during transactivation by HIF-1. Genes Dev. (1999) 13:64–75. 10.1101/gad.13.1.64
    1. Bamforth SD, Braganca J, Eloranta JJ, Murdoch JN, Marques FI, Kranc KR, et al. . Cardiac malformations, adrenal agenesis, neural crest defects and exencephaly in mice lacking Cited2, a new Tfap2 co-activator. Nat Genet. (2001) 29:469–74. 10.1038/ng768
    1. Kim G, Das R, Rao X, Zhong J, Deiuliis JA, Ramirez-Bergeron DL, et al. . CITED2 restrains proinflammatory macrophage activation and response. Mol Cell Biol. (2018) 38:e00452–17. 10.1128/MCB.00452-17
    1. Tien ES, Davis JW, Vanden HJ. Identification of the CREB-binding protein/p300-interacting protein CITED2 as a peroxisome proliferator-activated receptor alpha coregulator. J Biol Chem. (2004) 279:24053–63. 10.1074/jbc.M401489200
    1. Barber PA, Demchuk AM, Zhang J, Buchan AM. Validity and reliability of a quantitative computed tomography score in predicting outcome of hyperacute stroke before thrombolytic therapy. ASPECTS study group alberta stroke programme early CT score. Lancet. (2000) 355:1670–4. 10.1016/S0140-6736(00)02237-6
    1. Tan BYQ, Wan-Yee K, Paliwal P, Gopinathan A, Nadarajah M, Ting E, et al. . Good intracranial collaterals trump poor ASPECTS (alberta stroke program early CT score) for intravenous thrombolysis in anterior circulation acute ischemic stroke. Stroke. (2016) 47:2292–8. 10.1161/STROKEAHA.116.013879
    1. Yuanyuan D. The value of DWI-ASPECTS in predicting collateral circulation compensation in patients with acute middle cerebral artery infarction by intravenous thrombolysis. J Pract Med. (2018) 34:912–6. 10.3969/j.issn.1006-5725.2018.06.010
    1. Chinese guidelines for diagnoses and treatment of acute ischemic stroke 2018 . Chin J Neurol. (2018) 51:666–82. 10.3760/cma.j.issn.1006-7876.2018.09.004.1
    1. Song L, Lyu C, Shen G, Guo T, Wang J, Wang W, et al. . Application of FLAIR vascular hyperintensity-DWI mismatch in ischemic stroke depending on semi-quantitative DWI-alberta stroke program early CT score. Front Neurol. (2019) 10:994. 10.3389/fneur.2019.00994
    1. van der Hoeven EJ, McVerry F, Vos JA, Algra A, Puetz V, Kappelle LJ, et al. . Collateral flow predicts outcome after basilar artery occlusion: the posterior circulation collateral score. Int J Stroke. (2016) 11:768–75. 10.1177/1747493016641951
    1. Madelung CF, Ovesen C, Trampedach C, Christensen A, Havsteen I, Hansen CK, et al. . Leptomeningeal collateral status predicts outcome after middle cerebral artery occlusion. Acta Neurol Scand. (2018) 137:125–32. 10.1111/ane.12834
    1. Vagal A, Aviv R, Sucharew H, Reddy M, Hou Q, Michel P, et al. . Collateral clock is more important than time clock for tissue fate. Stroke. (2018) 49:2102–7. 10.1161/STROKEAHA.118.021484
    1. Braganca J, Eloranta JJ, Bamforth SD, Ibbitt JC, Hurst HC, Bhattacharya S. Physical and functional interactions among AP-2 transcription factors, p300/CREB-binding protein, and CITED2. J Biol Chem. (2003) 278:16021–9. 10.1074/jbc.M208144200
    1. Freedman SJ, Sun ZY, Kung AL, France DS, Wagner G, Eck MJ, et al. . Structural basis for negative regulation of hypoxia-inducible factor-1alpha by CITED2. Nat Struct Biol. (2003) 10:504–12. 10.1038/nsb936
    1. Fernandes MT, Calado SM, Mendes-Silva L, Bragança J. CITED2 and the modulation of the hypoxic response in cancer. World J Clin Oncol. (2020) 11:260–74. 10.5306/wjco.v11.i5.260
    1. Aljada A, O'Connor L, Fu YY, Mousa SA. PPAR gamma ligands, rosiglitazone and pioglitazone, inhibit bFGF- and VEGF-mediated angiogenesis. Angiogenesis. (2008) 11:361–7. 10.1007/s10456-008-9118-0
    1. Ai S, Cheng XW, Inoue A, Nakamura K, Okumura K, Iguchi A, et al. . Angiogenic activity of bFGF and VEGF suppressed by proteolytic cleavage by neutrophil elastase. Biochem Biophys Res Commun. (2007) 364:395–401. 10.1016/j.bbrc.2007.10.027
    1. MacDonald ST, Bamforth SD, Bragança J, Chen CM, Broadbent C, Schneider JE, et al. . A cell-autonomous role of Cited2 in controlling myocardial and coronary vascular development. Eur Heart J. (2013) 34:2557–65. 10.1093/eurheartj/ehs056
    1. Xiao S, Zhang D, Liu Z, Jin W, Huang G, Wei Z, et al. . Diabetes-induced glucolipotoxicity impairs wound healing ability of adipose-derived stem cells-through the miR-1248/CITED2/HIF-1α pathway. Aging. (2020) 12:6947–65. 10.18632/aging.103053
    1. Wang X, Lockhart SM, Rathjen T, Albadawi H, Sørensen D, O'Neill BT, et al. . Insulin downregulates the transcriptional coregulator CITED2, an inhibitor of proangiogenic function in endothelial cells. Diabetes. (2016) 65:3680–90. 10.2337/db16-0001
    1. Mor F, Quintana FJ, Cohen IR. Angiogenesis-inflammation cross-talk: vascular endothelial growth factor is secreted by activated T cells and induces Th1 polarization. J Immunol. (2004) 172:4618–23. 10.4049/jimmunol.172.7.4618
    1. Jin R, Yang G, Li G. Inflammatory mechanisms in ischemic stroke: role of inflammatory cells. J Leukoc Biol. (2010) 87:779–89. 10.1189/jlb.1109766
    1. Iadecola C, Anrather J. The immunology of stroke: from mechanisms to translation. Nat Med. (2011) 17:796–808. 10.1038/nm.2399
    1. Lucaciu A, Brunkhorst R, Pfeilschifter JM, Pfeilschifter W, Subburayalu J. The S1P-S1PR axis in neurological disorders-insights into current and future therapeutic perspectives. Cells. (2020) 9:1515. 10.3390/cells9061515
    1. Okamoto H, Takuwa N, Yokomizo T, Sugimoto N, Sakurada S, Shigematsu H, et al. . Inhibitory regulation of Rac activation, membrane ruffling, and cell migration by the G protein-coupled sphingosine-1-phosphate receptor EDG5 but not EDG1 or EDG3. Mol Cell Biol. (2000) 20:9247–61. 10.1128/MCB.20.24.9247-9261.2000
    1. Yu F, Feng X, Li X, Liu Z, Liao D, Wei M, et al. . Association of plasma metabolic biomarker sphingosine-1-phosphate with cerebral collateral circulation in acute ischemic stroke. Front Physiol. (2021) 12:720672. 10.3389/fphys.2021.720672
    1. Ceulemans AG, Zgavc T, Kooijman R, Hachimi-Idrissi S, Sarre S, Michotte Y. The dual role of the neuroinflammatory response after ischemic stroke: modulatory effects of hypothermia. J Neuroinflammation. (2010) 7:74. 10.1186/1742-2094-7-74
    1. Orr AW, Murphy-Ullrich JE. Regulation of endothelial cell function BY FAK and PYK2. Front Biosci. (2004) 9:1254–66. 10.2741/1239
    1. Woo KS, Chook P, Lolin YI, et al. . Hyperhomocyst(e)inemia is a risk factor for arterial endothelial dysfunction in humans. Circulation. (1997) 96:2542–4. 10.1161/01.CIR.96.8.2542
    1. Duan J, Murohara T, Ikeda H, Sasaki K, Shintani S, Akita T, et al. . Hyperhomocysteinemia impairs angiogenesis in response to hindlimb ischemia. Arterioscler Thromb Vasc Biol. (2000) 20:2579–85. 10.1161/01.atv.20.12.2579
    1. Velcheva I, Titianova E, Antonova N. Evaluation of the hemorheological and neurosonographic relationship in patients with cerebrovascular diseases. Clin Hemorheol Microcirc. (2004) 30:373–80. 10.1016/j.vph.2006.08.174
    1. Dan Li. Molecular weight fibrinogen variants determine angiogenesis rate in a fibrin matrix in vitro and in vivo. J Stroke Cerebrovasc Dis. (2020) 29:104991.
    1. Zang RS, Zhang H, Xu Y, Zhang SM, Liu X, Wang J, et al. . Serum C-reactive protein, fibrinogen and D-dimer in patients with progressive cerebral infarction. Transl Neurosci. (2016) 7:84–8. 10.1515/tnsci-2016-0013
    1. Shibuya M. VEGF-VEGFR system as a target for suppressing inflammation and other diseases. Endocr Metab Immune Disord Drug Targets. (2015) 15:135–44. 10.2174/1871530315666150316121956

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