Elevated Inflammatory Parameter Levels Negatively Impact Populations of Circulating Stem Cells (CD133+), Early Endothelial Progenitor Cells (CD133+/VEGFR2+), and Fibroblast Growth Factor in Stroke Patients

Author(s): Monika Golab-Janowska* , Edyta Paczkowska , Boguslaw Machalinski , Dariusz Kotlega , Agnieszka Meller , Krzysztof Safranow , Pawel Wankowicz , Przemyslaw Nowacki .

Journal Name: Current Neurovascular Research

Volume 16 , Issue 1 , 2019

Become EABM
Become Reviewer

Abstract:

Background: Endothelial Progenitor Cells (EPCs) are important players in neovascularization, mobilized through signalling by Angiogenic Growth Factors (AGFs) such as Vascular Endothelial Growth Factor (VEGF) and fibroblast growth factor (FGF). In vitro, inflammatory parameters impair the function and influence of EPCs on AGFs. However, this connection is not clear in vivo. To understand the mechanisms of augmented arteriogenesis and angiogenesis in acute ischemic stroke (AIS) patients, we investigated whether circulating stem cells (CD133+), early endothelial progenitor cells (CD133+/VEGFR2+), and endothelial cells (ECs; CD34¯/CD133¯/VEGFR2+) were increasingly mobilized during AIS, and whether there were correlations between EPC levels, growth factor levels and inflammatory parameters.

Methods: Data on demographics, classical vascular risk factors, neurological deficit information (assessed using the National Institutes of Health Stroke Scale), and treatment were collected from 43 consecutive AIS patients (group I). Risk factor control patients (group II) included 22 nonstroke subjects matched by age, gender, and traditional vascular risk factors. EPCs were measured by flow cytometry and the populations of circulating stem cells (CD133+), early EPCs (CD133+/VEGFR2+), and ECs (CD34¯/CD133¯/VEGFR2+) were analysed. Correlations between EPC levels and VEGF and FGF vascular growth factor levels as well as the influence of inflammatory parameters on EPCs and AGFs were assessed.

Results: Patient ages ranged from 54 to 92 years (mean age 75.2 ± 11.3 years). The number of circulating CD34¯/CD133¯/VEGF-R2+ cells was significantly higher in AIS patients than in control patients (p < 0.05). VEGF plasma levels were also significantly higher in AIS patients compared to control patients on day 7 (p < 0.05). FGF plasma levels in patients with AIS were significantly higher than those in the control group on day 3 (p < 0.05). There were no correlations between increased VEGF and FGF levels and the number of CD133+, CD133+/VEGFR2+, or CD34¯/CD133¯/VEGFR2+ cells. Leukocyte levels, FGF plasma levels, and the number of early EPCs were negatively correlated on day 3. High sensitivity C-reactive protein levels and the number of CD133+ and CD133+/VEGFR2+ cells were negatively correlated on day 7. In addition, there was a negative correlation between fibrinogen levels and FGF plasma levels as well as the number of early EPCs (CD133+/VEGFR2+).

Conclusion: AIS patients exhibited increased numbers of early EPCs (CD133+/VEGFR2+) and AGF (VEGF and FGF) levels. A negative correlation between inflammatory parameters and AGFs and EPCs indicated the unfavourable influence of inflammatory factors on EPC differentiation and survival. Moreover, these correlations represented an important mechanism linking inflammation to vascular disease.

Keywords: Stroke, circulating stem cells, early endothelial progenitor cells, inflammatory parameters, fibroblast growth factor, vascular endothelial growth factor.

[1]
Faralli A, Bigoni M, Mauro A, et al. Noninvasive strategies to promote functional recovery after stroke. Neural Plast 2013; 2013: 854597.
[2]
Ortega FJ, Jolkkonen J. Restorative therapies to enhance sensorimotor recovery following cerebral ischemia. Acta Neurobiol Exp 2013; 73: 66-78.
[3]
Peplow PV. Growth factor- and cytokine-stimulated endothelial progenitor cells in post-ischemic cerebral neovascularization. Neural Regen Res 2014; 9(15): 1425-9.
[4]
Shah PP, Szaflarski JP, Allendorfer J, Hamilton RH. Induction of neuroplasticity and recovery in post-stroke aphasia by non-invasive brain stimulation. Front Hum Neurosci 2013; 7: 888.
[5]
Risau W. Mechanisms of angiogenesis. Nature 1997; 386: 671-4.
[6]
Eguchi M, Masuda H, Asahara T. Endothelial progenitor cells for postnatal vasculogenesis. Clin Exp Nephrol 2007; 11: 18-25.
[7]
Luttun A, Carmeliet G, Carmeliet P. Vascular progenitors: From biology to treatment. Trends Cardiovasc Med 2002; 12: 88-96.
[8]
Rafii S, Lyden D, Benezra R, Hattori K, Heissig B. Vascular and haematopoietic stem cells: Novel targets for anti-angiogenesis therapy? Nat Rev Cancer 2002; 2: 826-35.
[9]
Asahara T, Isner JM. Endothelial progenitor cells for vascular regeneration. J Hematother Stem Cell Res 2002; 11: 171-8.
[10]
Rehman J, Li J, Orschell CM, March KL. Peripheral blood “endothelial progenitor cells” are derived from monocyte/macrophages and secrete angiogenic growth factors. Circulation 2003; 107: 1164-9.
[11]
Carmeliet P. Mechanisms of angiogenesis and arteriogenesis. Nat Med 2000; 6: 389-95.
[12]
Yancopoulos GD, Davis S, Gale NW, Rudge JS, Wiegand SJ, Holash J. Vascular-specific growth factors and blood vessel formation. Nature 2000; 407: 242-8.
[13]
Pepper MS, Ferrara N, Orci L, et al. Potent synergism between vascular endothelial growth factor and basic fibroblast growth factor in the induction of angiogenesis in vitro. Biochem Biophys Res Commun 1992; 189: 824-31.
[14]
Goto F, Goto K, Weindel K, et al. Synergistic effects of vascular endothelial growth factor and basic fibroblast growth factor on the proliferation and cord formation of bovine capillary endothelial cells within collagen gels. Lab Invest 1993; 69: 508-17.
[15]
Asahara T, Bauters C, Zheng LP, et al. Synergistic effect of vascular endothelial growth factor and basic fibroblast growth factor on angiogenesis in vivo. Circulation 1995; 92: II365-71.
[16]
Wilson JL, Hareendran A, Hendry A, et al. Reliability of the modified rankin scale across multiple raters: Benefits of a structured interview. Stroke 2005; 36(4): 777-8.
[17]
Kwah LK, Diogn J. National Institutes of Health Stroke Scale (NIHSS). J Physiother 2014; 60: 61.
[18]
Umetani K, Kodama Y, Nakamura T, et al. High prevalence of paroxysmal atrial fibrillation and/or atrial flutter in metabolic syndrome. Circ J 2007; 71: 252-5.
[19]
Ruiz Ortiz M, Romo E, Mesa D, et al. Predicting embolic events in patients with nonvalvular atrial fibrillation: Evaluation of the CHADS2 score in Mediterranean population. Rev Esp Cardiol 2008; 61: 29-35.
[20]
Olesen JB, Lip GY, Hansen ML, et al. Validation of risk stratification for predicting stroke and thromboembolism in atrial fibrillation nationwide cohort study. BMJ 2011; 342: d124.
[21]
Rehm J, Room R, Monteiro M, et al. Alcohol use. In: Comparative quantification of health risks: Global and regional burden of disease attributable to selected major risk factors . Ezzati M, Lopez AD, Rodgers A, Murrhay ChJL, Eds.. World Health Organization Geneva 2004; pp. 959-1108.
[22]
Umetani K, Kodama Y, Nakamura T, et al. High prevalence of paroxysmal atrial fibrillation and/or atrial flutter in metabolic syndrome. Circ J 2007; 71: 252-5.
[23]
Ay H, Furie KL, Singhal A, Smith WS, Sorensen AG, Koroshetz WJ. An evidence-based causative classification system for acute ischemic stroke. Ann Neurol 2005; 58: 688-97.
[24]
Yip HK, Chang LT, Chang WN, et al. Level and value of circulating endothelial progenitor cells in patients after acute ischemic stroke. Stroke 2008; 39: 69-74.
[25]
Yip HK, Tsai TH, Lin HS, et al. Effect of erythropoietin on level of circulating endothelial progenitor cells and outcome in patients after acute ischemic stroke. Crit Care 2011; 15: R40.
[26]
You D, Cochain C, Loinard C, et al. Combination of the angiotensin-converting enzyme inhibitor perindopril and the diuretic indapamide activate postnatal vasculogenesis in spontaneously hypertensive rats. J Pharmacol Exp Ther 2008; 325(3): 766-73.
[27]
Ghani U, Shuaib A, Salam A, et al. Endothelial progenitor cells during cerebrovascular disease. Stroke 2005; 36: 151-3.
[28]
Zhou WJ, Zhu DL, Yang GY, et al. Circulating endothelial progenitor cells in chinese patients with acute stroke. Hypertens Res 2009; 32: 306-31.
[29]
Dunac A, Frelin C, Popolo-Blondeau M, Chatel M, Mahagne MH, Philip PJ. Neurological and functional recovery in human stroke are associated with peripheral blood CD34+ cell mobilization. J Neurol 2007; 254: 327-32.
[30]
Paczkowska E, Gołąb-Janowska M, Bajer-Czajkowska A, et al. Increased circulating endothelial progenitor cells in patients with haemorrhagic and ischaemic stroke: the role of Endothelin-1. J Neurol Sci 2013; 325: 90-9.
[31]
Gołąb-Janowska M, Paczkowska E, Machaliński B, et al. Effects of angiotensin-converting enzyme inhibition on circulating endothelial progenitor cells in patients with acute ischemic stroke. Stem Cells Int 2018; 2018: 2827580.
[32]
Akita T, Murohara T, Ikeda H, et al. Hypoxic preconditioning augments efficacy of human endothelial progenitor cells for therapeutic neovascularization. Lab Invest 2003; 83: 65-73.
[33]
Carmeliet P, Moons L, Luttun A, et al. Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions. Nat Med 2001; 7: 575-83.
[34]
Guo H, Huang L, Cheng M, Jin X, Zhao Y, Yi M. Serial measurement of serum basic fibroblast growth factor in patients with acute cerebral infarction. Neurosci Lett 2006; 393: 56-9.
[35]
Asahara T, Takahashi T, Masuda H, et al. VEGF contributes to postnatal neovascularization by mobilizing bone marrow-derived endothelial progenitor cells. EMBO J 1999; 18(14): 3964-72.
[36]
Groger A, Piatkowski A, Grieb G, Wolter TP, Fuchs PC, Pallua N. The mobilisation of mononuclear cells and endothelial progenitor cells after burn injury in a porcine model. Burns 2010; 36(4): 545-51.
[37]
Langenberg MH, Nijkamp MW, Roodhart JM, et al. Liver surgery induces an immediate mobilization of progenitor cells in liver cancer patients: a potential role for G-CSF. Cancer Biol Ther 2010; 9(9): 743-8.
[38]
Slevin M, Krupinski J, Slowik A, Kumar P, Szczudlik A, Gaffney J. Serial measurement of vascular endothelial growth factor and transforming growth factor-beta1 in serum of patients with acute ischemic stroke. Stroke 2000; 31: 1863-70.
[39]
Matsuo R, Ago T, Kamouchi M, et al. Clinical significance of plasma VEGF value in ischemic stroke-research for biomarkers in ischemic stroke (REBIOS) study. BMC Neurol 2013; 13: 32.
[40]
Lee SC, Lee KY, Kim YJ, Kim SH, Koh SH, Lee YJ. Serum VEGF levels in acute ischaemic strokes are correlated with long-term prognosis. Eur J Neurol 2010; 17(1): 45-51.
[41]
Finkelstein SP, Apostolides PJ, Caday CG, Prosser J, Philips MF, Klagsbrun M. Increased basic fibroblast growth factor immunoreactivity at the site of focal brain wounds. Brain Res 1988; 460: 253-9.
[42]
Rafat N, Beck GCh, Peña-Tapia PG, Schmiedek P, Vajkoczy P. Increased levels of circulating endothelial progenitor cells in patients with Moyamoya disease. Stroke 2009; 40: 432-8.
[43]
Choi JH, Kim KL, Huh W, et al. Decreased number and impaired angiogenic function of endothelial progenitor cells in patients with chronic renal failure. Arterioscler Thromb Vasc Biol 2004; 24: 1246-52.
[44]
Sobrino T, Hurtado O, Moro MA, et al. The increase of circulating endothelial progenitor cells after acute ischemic stroke is associated with good outcome. Stroke 2007; 38: 2759-64.
[45]
Fadini GP, Miorin M, Facco M, et al. Circulating endothelial progenitor cells are reduced in peripheral vascular complications of type 2 diabetes mellitus. J Am Coll Cardiol 2005; 45: 1449-57.
[46]
Taguchi A, Soma T, Tanaka H, et al. Administration of CD34+ cells after stroke enhances neurogenesis via angiogenesis in a mouse model. J Clin Invest 2004; 114: 330-8.
[47]
Zhang ZG, Zhang L, Jiang Q, Chopp M. Bone marrow-derived endothelial progenitor cells participate in cerebral neovascularization after focal cerebral ischemia in the adult mouse. Circ Res 2002; 90: 284-8.
[48]
Westenbrink BD, Oeseburg H, Kleijn L, et al. Erythropoietin stimulates normal endothelial progenitor cell-mediated endothelial turnover, but attributes to neovascularization only in the presence of local ischemia. Cardiovasc Drugs Ther 2008; 22(4): 265-74.
[49]
Davidson EP, Coppey LJ, Holmes A, Yorek MA. Effect of inhibition of angiotensin converting enzyme and/or neutral endopeptidase on vascular and neural complications in high fat fed/low dose streptozotocin-diabetic rats. Eur J Pharmacol 2012; 677(1-3): 180-7.
[50]
Rückerl R, Peters A, Khuseyinova N, et al. Determinants of the acute-phase protein C-reactive protein in myocardial infarction survivors: the role of comorbidities and environmental factors. Clin Chem 2009; 55(2): 322-35.
[51]
Verma S, Kuliszewski MA, Li SH, et al. C-reactive protein attenuates endothelial progenitor cell survival, differentiation, and function: further evidence of a mechanistic link between C-reactive protein and cardiovascular disease. Circulation 2004; 109(17): 2058-67.
[52]
Turan RG, Brehm M, Koestering M, et al. Factors influencing spontaneous mobilization of CD34+ and CD133+ progenitor cells after myocardial infarction. Eur J Clin Invest 2007; 37: 842-51.
[53]
Guo M, Sahni SK, Sahni A, Francis CW. Fibrinogen regulates the expression of inflammatory chemokines through NF-kappaB activation of endothelial cells. Thromb Haemost 2004; 92(4): 858-66.
[54]
Thacker RI, Retzinger GS. Adsorbed fibrinogen regulates the behavior of human dendritic cells in a CD18-dependent manner. Exp Mol Pathol 2008; 84(2): 122-30.
[55]
Eidelman RS, Hennekens CH. Fibrinogen: A predictor of stroke and marker of atherosclerosis. Eur Heart J 2003; 24(6): 499-500.
[56]
Mandraffino G, Sardo MA, Riggio S, et al. Smoke exposure and circulating progenitor cells: evidence for modulation of antioxidant enzymes and cell count. Clin Biochem 2010; 43: 1436-42.
[57]
Mandraffino G, Aragona CO, Cairo V, et al. Circulating progenitor cells in hypertensive subjects: Effectiveness of a treatment with olmesartan in improving cell number and miR profile in addition to expected pharmacological effects. PLoS One 2017; 16: e0173030.


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 16
ISSUE: 1
Year: 2019
Page: [19 - 26]
Pages: 8
DOI: 10.2174/1567202616666190129164906
Price: $58

Article Metrics

PDF: 50
HTML: 2
EPUB: 1
PRC: 1