Generic placeholder image

Current Pharmaceutical Design


ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Review Article

Endothelial Dysfunction and Inflammation in Ischemic Stroke Pathogenesis

Author(s): ">Antonino Tuttolomondo*, ">Mario Daidone and ">Antonio Pinto

Volume 26, Issue 34, 2020

Page: [4209 - 4219] Pages: 11

DOI: 10.2174/1381612826666200417154126

Price: $65


Stroke is a heterogeneous disease, and within the broad category of brain ischemia and its subtypes vary dramatically in its etiology.

The endothelium can regulate the vascular homeostasis by modulating processes of vascular dilation and constriction by producing and secreting cytokines and chemical mediators, and inflammation represents one of the most important factors that contribute to alteration in vessel structure and function by dysregulation of this fine balance.

Endothelial dysfunction means a basic determinant of the vascular damage, which can be identified in all different clinical subtypes of stroke, and, recently, it has been recognized as an interesting determinant of cerebrovascular risk. The entire spectrum of inflammatory processes is likely to act in concert, and cytokines are important mediators of stroke by inducing immunological/inflammatory reactions, which contribute to brain infarct progression as well as to the disease severity and outcome.

Results from recent studies and ongoing and future researches will allow characterizing these complex mechanisms better and finally leading to innovative therapeutic strategies that may change the natural history of this severe and disabling disease significantly.

Keywords: Endothelium, inflammation, ischemic, stroke, vascular, cytokines.

Rajendran P, Rengarajan T, Thangavel J, et al. The vascular endothelium and human diseases. Int J Biol Sci 2013; 9(10): 1057-69.
[] [PMID: 24250251]
Park JB, Charbonneau F, Schiffrin EL. Correlation of endothelial function in large and small arteries in human essential hypertension. J Hypertens 2001; 19(3): 415-20.
[] [PMID: 11288811]
Schiffrin EL. A critical review of the role of endothelial factors in the pathogenesis of hypertension. J Cardiovasc Pharmacol 2001; 38(Suppl. 2): S3-6.
[] [PMID: 11811373]
Valentijn KM, Eikenboom J. Weibel-Palade bodies: a window to von Willebrand disease. J Thromb Haemost 2013; 11(4): 581-92.
[] [PMID: 23398618]
Peter L. Ridker Paul M, Maseri A. Inflammation and atherosclerosis. Circulation 2002; 105: 1135-43.
Korantzopoulos P, Letsas KP, Tse G, Fragakis N, Goudis CA, Liu T. Inflammation and atrial fibrillation: A comprehensive review. J Arrhythm 2018; 34(4): 394-401.
[] [PMID: 30167010]
Pinto A, Tuttolomondo A, Casuccio A, et al. . Immunoinflammatory predictors of stroke at follow-up in patients with chronic non-valvular atrial fibrillation (NVAF) Clin Sci Lond Engl 2009; 116: 781-9.
Raparelli V, Pastori D, Pignataro SF, et al. ARAPACIS Study Collaborators. Major adverse cardiovascular events in non-valvular atrial fibrillation with chronic obstructive pulmonary disease: the ARAPACIS study. Intern Emerg Med 2018; 13(5): 651-60.
[] [PMID: 29582316]
Gülke E, Gelderblom M, Magnus T. Danger signals in stroke and their role on microglia activation after ischemia. Ther Adv Neurol Disord 2018; 11.
Yang Y, Liu H, Zhang H, et al. st2/il-33-dependent microglial response limits acute ischemic brain injury. J Neurosci 2017; 37(18): 4692-704.
[] [PMID: 28389473]
David S, Kroner A. Repertoire of microglial and macrophage responses after spinal cord injury. Nat Rev Neurosci 2011; 12(7): 388-99.
[] [PMID: 21673720]
Perego C, Fumagalli S, De Simoni M-G. Temporal pattern of expression and colocalization of microglia/macrophage phenotype markers following brain ischemic injury in mice. J Neuroinflammation 2011; 8: 174.
[] [PMID: 22152337]
Ludewig P, Sedlacik J, Gelderblom M, et al. Carcinoembryonic antigen-related cell adhesion molecule 1 inhibits MMP-9-mediated blood-brain-barrier breakdown in a mouse model for ischemic stroke. Circ Res 2013; 113(8): 1013-22.
[] [PMID: 23780386]
Rosell A, Cuadrado E, Ortega-Aznar A, Hernández-Guillamon M, Lo EH, Montaner J. MMP-9-positive neutrophil infiltration is associated to blood-brain barrier breakdown and basal lamina type IV collagen degradation during hemorrhagic transformation after human ischemic stroke. Stroke 2008; 39(4): 1121-6.
[] [PMID: 18323498]
Garcia-Bonilla L, Moore JM, Racchumi G, et al. Inducible nitric oxide synthase in neutrophils and endothelium contributes to ischemic brain injury in mice. J Immunol 2014; 193(5): 2531-7.
[] [PMID: 25038255]
Dawson DA, Ruetzler CA, Carlos TM, Kochanek PM, Hallenbeck JM. Polymorphonuclear leukocytes and microcirculatory perfusion in acute stroke in the SHR. Keio J Med 1996; 45(3): 248-52.
[] [PMID: 8897768]
Cuartero MI, Ballesteros I, Moraga A, et al. N2 neutrophils, novel players in brain inflammation after stroke: modulation by the PPARγ agonist rosiglitazone. Stroke 2013; 44(12): 3498-508.
[] [PMID: 24135932]
Garcia-Bonilla L, Racchumi G, Murphy M, Anrather J, Iadecola C. endothelial cd36 contributes to postischemic brain injury by promoting neutrophil activation via CSF3. J Neurosci 2015; 35(44): 14783-93.
[] [PMID: 26538649]
Shichita T, Sugiyama Y, Ooboshi H, et al. Pivotal role of cerebral interleukin-17-producing gammadeltaT cells in the delayed phase of ischemic brain injury. Nat Med 2009; 15(8): 946-50.
[] [PMID: 19648929]
Gelderblom M, Weymar A, Bernreuther C, et al. Neutralization of the IL-17 axis diminishes neutrophil invasion and protects from ischemic stroke. Blood 2012; 120(18): 3793-802.
[] [PMID: 22976954]
Liesz A, Zhou W, Mracskó É, et al. Inhibition of lymphocyte trafficking shields the brain against deleterious neuroinflammation after stroke. Brain 2011; 134(Pt 3): 704-20.
[] [PMID: 21354973]
Sakaguchi S, Miyara M, Costantino CM, Hafler DA. FOXP3+ regulatory T cells in the human immune system. Nat Rev Immunol 2010; 10(7): 490-500.
[] [PMID: 20559327]
Liesz A, Suri-Payer E, Veltkamp C, et al. Regulatory T cells are key cerebroprotective immunomodulators in acute experimental stroke. Nat Med 2009; 15(2): 192-9.
[] [PMID: 19169263]
Liesz A, Zhou W, Na S-Y, et al. Boosting regulatory T cells limits neuroinflammation in permanent cortical stroke. J Neurosci 2013; 33(44): 17350-62.
[] [PMID: 24174668]
Ito M, Komai K, Mise-Omata S, et al. Brain regulatory T cells suppress astrogliosis and potentiate neurological recovery. Nature 2019; 565(7738): 246-50.
[] [PMID: 30602786]
Xu X, Li M, Jiang Y. The paradox role of regulatory T cells in ischemic stroke. ScientificWorldJournal 2013; 2013: 174373.
[] [PMID: 24288462]
Tuttolomondo A, Pecoraro R, Casuccio A, et al. Peripheral frequency of CD4+ CD28- cells in acute ischemic stroke: relationship with stroke subtype and severity markers. Medicine (Baltimore) 2015; 94(20): e813.
[] [PMID: 25997053]
Winek K, Engel O, Koduah P, et al. Depletion of cultivatable gut microbiota by broad-spectrum antibiotic pretreatment worsens outcome after murine stroke. Stroke 2016; 47(5): 1354-63.
[] [PMID: 27056982]
Benakis C, Brea D, Caballero S, et al. Commensal microbiota affects ischemic stroke outcome by regulating intestinal γδ T cells. Nat Med 2016; 22(5): 516-23.
[] [PMID: 27019327]
Yamashiro K, Tanaka R, Urabe T, et al. Gut dysbiosis is associated with metabolism and systemic inflammation in patients with ischemic stroke. PLoS One 2017; 12(2): e0171521.
[] [PMID: 28166278]
Yin J, Liao S-X, He Y, et al. Dysbiosis of gut microbiota with reduced trimethylamine-n-oxide level in patients with large-artery atherosclerotic stroke or transient ischemic attack. J Am Heart Assoc 2015; 4(11): e002699.
[] [PMID: 26597155]
Ji W, Zhu Y, Kan P, et al. Analysis of intestinal microbial communities of cerebral infarction and ischemia patients based on high throughput sequencing technology and glucose and lipid metabolism. Mol Med Rep 2017; 16(4): 5413-7.
[] [PMID: 28849032]
Vamanu E. Complementary functional strategy for modula-tion of human gut microbiota. Curr Pharm Des 2018; 24(35): 4144-9.
Yu E, Hsu H-Y, Huang C-Y, Hwang L-C. Inflammatory biomarkers and risk of atherosclerotic cardiovascular disease. Open Med (Wars) 2018; 13: 208-13.
[] [PMID: 29845121]
Shrivastava AK, Singh HV, Raizada A, Singh SK. C-reactive protein, inflammation and coronary heart disease. Egypt Heart J 2015; 67: 89-97.
Kamath DY, Xavier D, Sigamani A, Pais P. High sensitivity Creactive protein (hsCRP) & cardiovascular disease: An Indian perspective. Indian J Med Res 2015; 142(3): 261-8.
[] [PMID: 26458341]
Ladenvall C, Jood K, Blomstrand C, Nilsson S, Jern C, Ladenvall P. Serum C-reactive protein concentration and genotype in relation to ischemic stroke subtype. Stroke 2006; 37(8): 2018-23.
[] [PMID: 16809555]
Piccardi B, Giralt D, Bustamante A, et al. Blood markers of inflammation and endothelial dysfunction in cardioembolic stroke: systematic review and meta-analysis Biomark Biochem Indic Expo Response Susceptibility Chem 22: 200-9.
Kuhlmann CRW, Librizzi L, Closhen D, et al. Mechanisms of Creactive protein-induced blood-brain barrier disruption. Stroke 2009; 40(4): 1458-66.
[] [PMID: 19246692]
Welsh P, Barber M, Langhorne P, Rumley A, Lowe GDO, Stott DJ. Associations of inflammatory and haemostatic biomarkers with poor outcome in acute ischaemic stroke. Cerebrovasc Dis 2009; 27(3): 247-53.
[] [PMID: 19176958]
Idicula TT, Brogger J, Naess H, Waje-Andreassen U, Thomassen L. Admission C-reactive protein after acute ischemic stroke is associated with stroke severity and mortality: the ‘Bergen stroke study’. BMC Neurol 2009; 9: 18.
[] [PMID: 19400931]
Matsuo R, Ago T, Hata J, et al. Fukuoka stroke registry investigators. plasma c-reactive protein and clinical outcomes after acute ischemic stroke: a prospective observational study. PLoS One 2016; 11(6): e0156790.
[] [PMID: 27258004]
Liu T, Clark RK, McDonnell PC, et al. Tumor necrosis factor-alpha expression in ischemic neurons. Stroke 1994; 25(7): 1481-8.
[] [PMID: 8023366]
Rosenberg GA, Estrada EY, Dencoff JE, Stetler-Stevenson WG. Tumor necrosis factor-alpha-induced gelatinase B causes delayed opening of the blood-brain barrier: an expanded therapeutic window. Brain Res 1995; 703(1-2): 151-5.
[] [PMID: 8719627]
Rosenberg GA, Navratil M, Barone F, Feuerstein G. Proteolytic cascade enzymes increase in focal cerebral ischemia in rat. J Cereb Blood Flow Metab 1996; 16(3): 360-6.
[] [PMID: 8621740]
Selmaj KW, Raine CS. Tumor necrosis factor mediates myelin and oligodendrocyte damage in vitro. Ann Neurol 1988; 23(4): 339-46.
[] [PMID: 3132891]
Selmaj KW, Farooq M, Norton WT, Raine CS, Brosnan CF. Proliferation of astrocytes in vitro in response to cytokines. A primary role for tumor necrosis factor. J Immunol 1990; 144(1): 129-35.
[PMID: 2104886]
Stellwagen D, Beattie EC, Seo JY, Malenka RC. Differential regulation of AMPA receptor and GABA receptor trafficking by tumor necrosis factor-alpha. J Neurosci 2005; 25(12): 3219-28.
[] [PMID: 15788779]
Weber C, Erl W, Pietsch A, Ströbel M, Ziegler-Heitbrock HW, Weber PC. Antioxidants inhibit monocyte adhesion by suppressing nuclear factor-kappa B mobilization and induction of vascular cell adhesion molecule-1 in endothelial cells stimulated to generate radicals. Arterioscler Thromb 1994; 14(10): 1665-73.
[] [PMID: 7522548]
Barone FC, Arvin B, White RF, et al. Tumor necrosis factor-alpha. A mediator of focal ischemic brain injury. Stroke 1997; 28(6): 1233-44.
[] [PMID: 9183357]
Tuttolomondo A, Di Sciacca R, Di Raimondo D, et al. Plasma levels of inflammatory and thrombotic/fibrinolytic markers in acute ischemic strokes: relationship with TOAST subtype, outcome and infarct site. J Neuroimmunol 2009; 215(1-2): 84-9.
[] [PMID: 19695716]
Ridker PM, Everett BM, Pradhan A, et al. CIRT Investigators Low-dose methotrexate for the prevention of atherosclerotic events. N Engl J Med 2019; 380(8): 752-62.
[] [PMID: 30415610]
Tardif J-C, Kouz S, Waters DD, et al. Efficacy and safety of low-dose colchicine after myocardial infarction. N Engl J Med 2019; 381(26): 2497-505.
[] [PMID: 31733140]
Ridker PM, Everett BM, Thuren T, et al. CANTOS Trial Group Antiinflammatory therapy with Canakinumab for atherosclerotic disease. N Engl J Med 2017; 377(12): 1119-31.
[] [PMID: 28845751]
Tobinick E, Kim NM, Reyzin G, Rodriguez-Romanacce H, DePuy V. Selective TNF inhibition for chronic stroke and traumatic brain injury: an observational study involving 629 consecutive patients treated with perispinal etanercept. CNS Drugs 2012; 26(12): 1051-70.
[] [PMID: 23100196]
Sumbria RK, Boado RJ, Pardridge WM. Brain protection from stroke with intravenous TNFα decoy receptor-Trojan horse fusion protein. J Cereb Blood Flow Metab 2012; 32(10): 1933-8.
[] [PMID: 22714051]
Smith CJ, Hulme S, Vail A, et al. SCIL-STROKE (Subcutaneous Interleukin-1 Receptor Antagonist in Ischemic Stroke): A randomized controlled phase 2 trial. Stroke 2018; 49(5): 1210-6.
[] [PMID: 29567761]
Elrayess MA, Webb KE, Flavell DM, et al. A novel functional polymorphism in the PECAM-1 gene (53G>A) is associated with progression of atherosclerosis in the LOCAT and REGRESS studies. Atherosclerosis 2003; 168(1): 131-8.
[] [PMID: 12732396]
Elrayess MA, Talmud PJ. Platelet endothelial cell adhesion molecule-1 (PECAM-1) & coronary heart disease. Indian J Med Res 2005; 121(2): 77-9.
[PMID: 15756038]
Wei Y-S, Lan Y, Liu Y-G, Meng L-Q, Xu Q-Q, Xie H-Y. Plateletendothelial cell adhesion molecule-1 gene polymorphism and its soluble level are associated with ischemic stroke. DNA Cell Biol 2009; 28(3): 151-8.
[] [PMID: 19183069]
Castellanos M, Castillo J, García MM, et al. Inflammationmediated damage in progressing lacunar infarctions: a potential therapeutic target. Stroke 2002; 33(4): 982-7.
[] [PMID: 11935048]
Wiseman S, Marlborough F, Doubal F, Webb DJ, Wardlaw J. Blood markers of coagulation, fibrinolysis, endothelial dysfunction and inflammation in lacunar stroke versus non-lacunar stroke and non-stroke: systematic review and meta-analysis. Cerebrovasc Dis 2014; 37(1): 64-75.
[] [PMID: 24401164]
Arba F, Giannini A, Piccardi B, et al. Small vessel disease and biomarkers of endothelial dysfunction after ischaemic stroke. Eur Stroke J 2019; 4(2): 119-26.
[] [PMID: 31259260]
Bongers TN, de Maat MPM, van Goor M-LPJ, et al. High von Willebrand factor levels increase the risk of first ischemic stroke: influence of ADAMTS13, inflammation, and genetic variability. Stroke 2006; 37(11): 2672-7.
[] [PMID: 16990571]
Hanson E, Jood K, Karlsson S, Nilsson S, Blomstrand C, Jern C. Plasma levels of von Willebrand factor in the etiologic subtypes of ischemic stroke. J Thromb Haemost 2011; 9(2): 275-81.
[] [PMID: 21054779]
Oz F, Elitok A, Bilge AK, Mercanoglu F, Oflaz H. Relationship between brachial artery flow-mediated dilation, carotid artery intima-media thickness and coronary flow reserve in patients with coronary artery disease. Cardiol Res 2012; 3(5): 214-21.
[] [PMID: 28348690]
Halcox JPJ, Donald AE, Ellins E, et al. Endothelial function predicts progression of carotid intima-media thickness. Circulation 2009; 119(7): 1005-12.
[] [PMID: 19204308]
Yeboah J, Crouse JR, Bluemke DA, et al. Endothelial dysfunction is associated with left ventricular mass (assessed using MRI) in an adult population (MESA). J Hum Hypertens 2011; 25(1): 25-31.
[] [PMID: 20237502]
Sancheti S, Shah P, Phalgune DS. Correlation of endothelial dysfunction measured by flow-mediated vasodilatation to severity of coronary artery disease. Indian Heart J 2018; 70(5): 622-6.
[] [PMID: 30392498]
Green DJ, Jones H, Thijssen D, Cable NT, Atkinson G. Flowmediated dilation and cardiovascular event prediction: does nitric oxide matter? Hypertens Dallas Tex 2011; 57: 363-9.
Inaba Y, Chen JA, Bergmann SR. Prediction of future cardiovascular outcomes by flow-mediated vasodilatation of brachial artery: a meta-analysis. Int J Cardiovasc Imaging 2010; 26(6): 631-40.
[] [PMID: 20339920]
Santos-García D, Blanco M, Serena J, et al. Brachial arterial flow mediated dilation in acute ischemic stroke. Eur J Neurol 2009; 16(6): 684-90.
[] [PMID: 19236459]
Santos-García D, Blanco M, Serena J, Rodríguez-Yáñez M, Leira R, Castillo J. Impaired brachial flow-mediated dilation is a predictor of a new-onset vascular event after stroke. Cerebrovasc Dis 2011; 32(2): 155-62.
[] [PMID: 21778713]
Rubinshtein R, Kuvin JT, Soffler M, et al. Assessment of endothelial function by non-invasive peripheral arterial tonometry predicts late cardiovascular adverse events. Eur Heart J 2010; 31(9): 1142-8.
[] [PMID: 20181680]
Tuttolomondo A, Casuccio A, Della Corte V, et al. Endothelial function and arterial stiffness indexes in subjects with acute ischemic stroke: Relationship with TOAST subtype. Atherosclerosis 2017; 256: 94-9.
[] [PMID: 27817840]
Bellien J, Favre J, Iacob M, et al. Arterial stiffness is regulated by nitric oxide and endothelium-derived hyperpolarizing factor during changes in blood flow in humans. Hypertension 2010; 55(3): 674-80.
[] [PMID: 20083732]
Mancia G, Laurent S, Agabiti-Rosei E, et al. European Society of Hypertension. Reappraisal of European guidelines on hypertension management: a European Society of Hypertension Task Force document. J Hypertens 2009; 27(11): 2121-58.
[] [PMID: 19838131]
Bonarjee VVS. Available methods and clinical application. arterial stiffness: a prognostic marker in coronary heart disease. Front Cardiovasc Med 2018; 5: 64.
[] [PMID: 29951487]
Scandale G, Dimitrov G, Recchia M, et al. Arterial stiffness and 5-year mortality in patients with peripheral arterial disease. J Hum Hypertens 2019; 34: 505-44.
[] [PMID: 31548619]
Tuttolomondo A, Di Raimondo D, Di Sciacca R, et al. Arterial stiffness and ischemic stroke in subjects with and without metabolic syndrome. Atherosclerosis 2012; 225(1): 216-9.
[] [PMID: 23031362]
Dimitriadis K, Tsioufis C, Kasiakogias A, et al. Arterial stiffness independently predicts stroke in patients with essential hypertension: data from a greek 8-year-follow-up study. J Hypertens 2017; 36.
Taddei S, Bruno RM. Endothelial dysfunction in hypertension: achievements and open questions. J Hypertens 2016; 34(8): 1492-3.
[] [PMID: 27355996]
Jean D. Ganz Peter. Role of Endothelial Dysfunction in Atherosclerosis. Circulation 2004; 109: III-27- III-32.
Kinlay S, Ganz P. Relation between endothelial dysfunction and the acute coronary syndrome: implications for therapy. Am J Cardiol 2000; 86(8B): 10J-3.
[] [PMID: 11081444]
Tuttolomondo A, Maida C, Pinto A. Diabetic foot syndrome: Immune-inflammatory features as possible cardiovascular markers in diabetes. World J Orthop 2015; 6(1): 62-76.
[] [PMID: 25621212]
Wong VW, Petta S, Hiriart JB, et al. Validity criteria for the diagnosis of fatty liver by M probe-based controlled attenuation parameter. J Hepatol 2017; 67(3): 577-84.
[] [PMID: 28506907]
Violi F, Corazza GR, Caldwell SH, et al. PRO-LIVER Collaborators Portal vein thrombosis relevance on liver cirrhosis: Italian Venous Thrombotic Events Registry. Intern Emerg Med 2016; 11(8): 1059-66.
[] [PMID: 27026379]
Tuttolomondo A, Pinto A, Corrao S, et al. Immuno-inflammatory and thrombotic/fibrinolytic variables associated with acute ischemic stroke diagnosis. Atherosclerosis 2009; 203(2): 503-8.
[] [PMID: 18715563]
Albanese A, Tuttolomondo A, Anile C, et al. Spontaneous chronic subdural hematomas in young adults with a deficiency in coagulation factor XIII. Report of three cases. J Neurosurg 2005; 102(6): 1130-2.
[] [PMID: 16028774]
Di Raimondo D, Tuttolomondo A, Buttà C, et al. Metabolic and anti-inflammatory effects of a home-based programme of aerobic physical exercise. Int J Clin Pract 2013; 67(12): 1247-53.
[] [PMID: 24246205]
Tuttolomondo A, Maida C, Pinto A. Diabetic foot syndrome as a possible cardiovascular marker in diabetic patients. J Diabetes Res 2015; 2015: 268390.
[] [PMID: 25883983]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy