Clinical and experimental studies have been focused on the pathophysiological mechanisms induced by brain ischemia-reperfusion injury. Recovery events, such as neurogenesis, angiogenesis and the growth of new blood vessels from the preexisting vascular tree, have been intensively studied in the last decades to clarify the vascular remodeling crucial for stroke outcome. This review aims to discuss the cerebral microcirculation remodeling induced by ischemia-reperfusion and the mechanisms involved in angiogenesis and vasculogenesis. The first in vivo observations were focused on anastomotic shunting of cerebral blood flow (CBF) in experimental and clinical models. Thereafter, vascular remodeling induced by cerebral ischemia-reperfusion was reported in mice and rats. Successively, other studies have assessed that within 30 days of middle cerebral artery (MCA) occlusion in rats, there is an increase in CBF and recovery from stroke. Recently, rats submitted to transient MCA occlusion showed pial microcirculation remodeling with the formation of new arterioles sprouting from penumbra vessels and overlapping the ischemic core. This review focuses on the production and/or activation of vasculotrophic factors able to trigger and facilitate microvascular remodeling. Vascular endothelial growth factor and endothelium-released nitric oxide appear to be the main factors involved in the formation of new vessels during microvascular remodeling. These studies are fundamental for consequent interventions on molecular targets, useful for fostering vascular remodeling and the recovery of functions.

1.
Hennerici MG, Kern R, Szabo K: Non-pharmacological strategies for the treatment of acute ischaemic stroke. Lancet Neurol 2013;12:572-584.
2.
Zhang L, Zhang ZG, Chopp M: The neurovascular unit and combination treatment strategies for stroke. Trends Pharmacol Sci 2012;33:415-422.
3.
Reza Noorian A, Nougeira R, Gupta R: Neuroprotection in acute ischemic stroke. J Neurosurg Sci 2011;55:127-138.
4.
Hung CW, Liou YJ, Lu SW, Tseng LM, Kao CL, Chen SJ, Chiou SH, Chang CJ: Stem cell-based neuroprotective and neurorestorative strategies. Int J Mol Sci 2010;11:2039-2055.
5.
Vidal SM, Chaudhry FS, Schneck M: Management of acute ischemic stroke. Hosp Pract 2013;41:108-122.
6.
Zaidat OO, Lazzaro MA, Liebeskind DS, Janjua N, Wechsler L, Nogueira RG, Edgell RC, Kalia JS, Badruddin A, English J, Yavagal D, Kirmani JF, Alexandrov AV, Khatri P: Revascularization grading in endovascular acute ischemic stroke therapy. Neurology 2012;25:79.
7.
DeMers G, Meurer WJ, Shih R, Rosenbaum S, Vilke GM: Tissue plasminogen activator and stroke: review of the literature for the clinician. J Emerg Med 2012;43:1149-1154.
8.
Chen J, Chopp M: Neurorestorative treatment of stroke: cell and pharmacological approaches. NeuroRx 2006;3:466-473.
9.
Zhang ZG, Chopp M: Neurorestorative therapies for stroke: underlying mechanisms and translation to the clinic. Lancet Neurol 2009;8:491-500.
10.
Scianna M, Bell CG, Preziosi L: A review of mathematical models for the formation of vascular networks. J Theor Biol 2013;333:174-209.
11.
Liman TG, Endres M: New vessels after stroke: postischemic neovascularisation and regeneration. Cerebrovasc Dis 2012;33:492-499.
12.
Gibbons GH, Dzau VJ: The emerging concept of vascular remodeling. N Engl J Med 1994;330:1431-1438.
13.
Morris PP, Choi IS: Cerebral vascular anatomy. Neuroimaging Clin N Am 1996;6:541-560.
14.
Tam SJ, Watts RJ: Connecting vascular and nervous system development: angiogenesis and the blood-brain barrier. Annu Rev Neurosci 2010;33:379-408.
15.
Rhoton AL: The cerebrum. Anat Neurosurg 2007;61:37-118.
16.
Schmidt CF: Central nervous system circulation, fluid and barriers; in Field J (ed): Handbook of Physiology, vol 3. Washington, American Physiological Society, 1960, pp 1745-1750.
17.
Vogel AC, Power JD, Petersen SE, Schlaggar BL: Development of the brain's functional network architecture. Neuropsychol Rev 2010;20:362-375.
18.
Vasoncelos C, Xavier J, Almeida-Pinto J, Cruz R: Vascularization of the skull base-review of the literature and illustrative cases. Acta Med Port 2001;14:33-42.
19.
Rogers L: The function of the circulus arteriosus of Wills. Brain 1947;70:171-178.
20.
Fagundes DJ, Taha MO: Animal disease model: choice's criteria and current animals specimens. Acta Cir Bras 2004;19:59-65.
21.
Sicard KM, Fisher M: Animal models of focal brain ischemia. Exp Transl Stroke Med 2009;1:7.
22.
McBean DE, Kelly PAT: Rodent models of global cerebral ischemia: a comparision of two-vessel occlusion and four-vessel occlusion. Gen Pharmac 1998;4:431-434.
23.
Krafft PR, Bailey EL, Lekic T, Rolland WB, Altay O, Tang J, Wardlaw JM, Zhang JH, Sudlow CL: Etiology of stroke and choice of models. Int J Stroke 2012;7:398-496.
24.
Traystman RJ: Animal models of focal and global cerebral ischemia. ILAR J 2003;44:85-95.
25.
Garcia JH: Experimental ischemic stroke: a review. Stroke 1984;15:5-14.
26.
Eklof B, Siesjo BK: The effect of bilateral common carotid artery ligation upon the blood flow and energy state of the rat brain. Acta Physiol Scand 1972;86:155-165.
27.
Pulsinelli WA, Brierly JB: A new model of bilateral hemispheric ischemia in the unanesthetized rat. Stroke 1979;10:267-272.
28.
Smith ML, Bendek G, Dahlgren N, Rosèn I, Wielok T, Siesjo BK: Models for studying long-term recovery following forebrain ischemia in the rat. 2. A 2-vessel occlusion model. Acta Neurol Scand 1984;69:385-401.
29.
Smith ML, Auer RN, Smith ML: The density and distribution of ischemic brain injury in the rat following 2-10 min of forebrain ischemia. Acta Neuropathol (Berl) 1984;64:319-332.
30.
Kågstrom E, Smith ML, Smith ML: Recirculation in the rat brain following incomplete ischemia. J Cereb Blood Flow Metab 1983;3:183-192.
31.
Busto R, Dietrich WD, Globus MYT, Ginsberg MD: postischemic moderate hypothermia inhibits CA1 hippocampal ischemic neuronal injury. Neurosci Lett 1989;101:299-304.
32.
Iwasaki Y, Ito S, Suzuki M, Nagahori T, Yamamoto T, Konno H: Forebrain ischemia induced by temporary bilateral common carotid occlusion in normotensive rats. J Neurol Sci 1989;90:155-165.
33.
Chan PH: Role of oxidant in ischemic brain damage. Stroke 1996;27:1124-1129.
34.
Nakashima M, Niwa M, Iwai T, Uematsu T: Involvement of free radicals in cerebrovascular reperfusion injury evaluated in a transient focal cerebral ischemia model of rat. Free Radic Biol Med 1999;26:722-729.
35.
Cho JY, Kim IS, Jang YH, Kim AR, Lee SR: Protective effects of quercetin, a natural flavonoid against neuronal damage after transient global cerebral ischemia. Neurosci Lett 2006;404:330-335.
36.
Lapi D, Marchiafava PL, Colantuoni A: Pial microvascular responses to transient bilateral common carotid artery occlusion: effects of hypertonic glycerol. J Vasc Res 2008;45:89-102.
37.
Lapi D, Vagnani S, Pignataro G, Esposito E, Paterni M, Colantuoni A: Protective effects of quercetin on rat pial microvascular changes during transient bilateral common carotid artery occlusion and reperfusion. Front Physiol 2012;3:32.
38.
Lapi D, Vagnani S, Cardaci E, Paterni M, Colantuoni A: Rat pial microvascular responses to melatonin during bilateral common carotid artery occlusion and reperfusion. J Pineal Res 2011;51:136-144.
39.
Pulsinelli WA, Levy DE, Duffy TE: regional cerebral blood flow and glucose metabolism following transient forebrain ischemia. Ann Neurol 1982;11:499-509.
40.
Ginsberg MD: Loval brain blood flow-metabolism interrelationships in an experimental model of diffuse cerebral ischemia. Cereb Vasc Dis 1981;3:195-200.
41.
Shigeno T, Teasdale GM, McCulloch J, Graham DI: Recirculation model following MCA occlusion in rats. J Neurosurg 1985;63:272-277.
42.
Heiss WD: The ischemic penumbra: how does tissue injury evolve? Ann NY Acad Sci 2012;1268:26-34.
43.
Longa EZ, Weinstein PR, Carlson S, Cummins R: Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 1989;20:84-91.
44.
Garcia JH, Yoshida Y, Chen H, Li Y, Zhang ZG, Lian J, Chen S, Chopp M: Progression from ischemic injury to infarct following middle cerebral artery occlusion in the rat. Am J Pathol 1993;142:623-635.
45.
Watson BD, Dietrich WD, Busto R, Wachtel MS, Ginsberg MD: Induction of reproducible brain infarction by photochemically initiated thrombosis. Ann Neurol 1985;17:497-504.
46.
Risau W: Mechanisms of angiogenesis. Nature 1997;386:671-674.
47.
Simons M: Angiogenesis: where do we stand now? Circulation 2005;111:1556-1566.
48.
Beck H, Plate KH: Angiogenesis after cerebral ischemia. Acta Neuropathol 2009;117:481-496.
49.
Ware JA, Simons M: Angiogenesis in ischemic heart disease. Nat Med 1997;3:158-164.
50.
Wurzel J, Goldman BH: Angiogenesis factors in acute myocardial ischemia and infarction. N Engl J Med 2000;343:148-149.
51.
Yamashita T, Nimomiva M, Hernandez AP: Subventricular zone-derived neuroblast migrate and differentiate into mature neurons in the post-stroke adult striatum. J Neurosci 2006;26:6627-6636.
52.
Meyer JS, Denny-Brown D: Studies of cerebral circulation in brain injury. II. Cerebral concussion. Electroencephalogr Clin Neurophysiol 1955;7:529-544.
53.
Halsey JH, Clark LC: Some regional circulatory abnormalities following experimental cerebral infarction. Neurology 1970;20:238-246.
54.
Coyle P, Heistad DD: Blood flow through cerebral collateral vessels one month after middle cerebral artery occlusion. Stroke 1987;18:407-411.
55.
Coyle P, Heistad DD: Development of collaterals in the cerebral circulation. Blood Vessels 1991;28:183-189.
56.
van den Akker J, Schoorl MJ, Bakker EN, Vanbavel E: Small artery remodelling: current concepts and questions. J Vasc Res 2010;47:183-202.
57.
Krupinski J, Kaluzza J, Kumar P, Kumar S, Wang JM: Role of angiogenesis in patients with cerebral ischemic stroke. Stroke 1994;25:1794-1798.
58.
Szpak GM, Lechwicz W, Lewandowska E, Bertrand E, Wierzba-Bobrowicz T, Dymecki J: Border zone neovascularization in cerebral ischemic infarct. Folia Neuropathol 1999;37:264-268.
59.
Wei L, Erinjeri JP, Rovainen CM, Woolsey TA: Collateral growth and angiogenesis around cortical stroke. Stroke 2001;32:2179-2184.
60.
Hayashi T, Noshita N, Sugawara T, Chan PH: Temporal profile of angiogenesis and expression of related genes in the brain after ischemia. J Cereb Blood Flow Metab 2003;23:166-180.
61.
Ayata C, Dunn AK, Gursoy-Ozdemir Y, Huang Z, Boas DA, Moskowitz MA: Laser speckle flowmetry for the study of cerebrovascular physiology in normal and ischemic mouse cortex. J Cereb Blood Flow Metab 2004;24:744-755.
62.
Tomita Y, Kubis N, Calando Y, Dinh AT, Mèric P, Seylaz J, Pinard E: Long-term in vivo investigation of mouse cerebral microcirculation by fluorescence confocal microscopy in the area of focal ischemia. J Cereb Blood Flow Metab 2005;25:858-867.
63.
Toriumi H, Tatarishvili J, Tomita M, Tomita Y, Unekawa M, Suzuki N: Dually supplied T-junction in arterio-arteriolar anastomosis in mice: key to local hemodynamic homeostasis in normal and ischemic states? Stroke 2009;40:3378-3383.
64.
Coyle P, Jokelainen PT: Dorsal cerebral arterial collaterals of the rat. Anat Rec 1982;203:397-404.
65.
Tomita Y, Pinard E, Tran-dinh A, Schiszler I, Kubis N, Tomita M, Suzuki N, Seylaz J: Long-term, repeated measurements of mouse cortical microflow at the same region of interest with high spatial resolution. Brain Res 2011;1372:59-69.
66.
Mostany R, Chowdhury TG, Johnston DG, Potonovo SA, Carmichael ST, Portera-Cailliau C: local hemodynamics dictate long-term dendritic plasticity in peri-infarct cortex. J Neurosci 2010;30:14116-14126.
67.
Lapi D, Vagnani S, Sapio D, Mastantuono T, Sabatino L, Paterni M, Colantuoni A: Long-term of rat pial microcirculation after transient middle cerebral artery occlusion and reperfusion. J Vasc Res 2013;50:332-345.
68.
Kuchan MJ, Frangos JA: Shear stress regulates endothelin-1 release via protein kinase C and cGMP in cultured endothelial cells. Ann J Physiol 1993;264:H150-H156.
69.
Demougeot C, Van Hoecke M, Bertrand N, Prigent-Tessier A, Mossiat C, Beley A, Marie C: Cytoprotective efficacy and mechanisms of the liposoluble iron chelator 2,2'-dipyridyl in the rat photothrombotic ischemic stroke model. J Pharmacol Exp Ther 2004;311:1080-1087.
70.
Li SF, Wang RZ, Li GL: Recent advance in experimental study of cerebral ischemia treated by vascular endothelial growth factor. Zhongguo Yi Xue Ke Xue Yuan Xue Bao 2005;27:115-119.
71.
Sun Y, Jin K, Xie L, Childs J, Mao XO, Logvinova A, Greenberg DA: VEGF-induced neuroprotection, neurogenesis, and angiogenesis after focal cerebral ischemia. J Clin Invest 2003;111:1843-1851.
72.
Iadecola C, Zhang F, Xu S, Casey R, Ross ME: Inducible nitric oxide synthase gene expression in brain following cerebral ischemia. J Cereb Blood Flow Metab 1995;15:378-384.
73.
Plate KH, Beck H, Danner S, Allegrini PR, Wiessner C: Cell type specific upregulation of vascular endothelial growth factor in an MCA-occlusion model of cerebral infarct. J Neuropathol Exp Neurol 1999;58:654-666.
74.
Pettersson A, Nagy JA, Brown LF, Sundberg C, Morgan E, Jungles S, Carter R, Krieger JE, Manseau EJ, Harvey VS, Eckelhoefer IA, Feng D, Dvorak AM, Mulligan RC, Dvorak HF: Heterogeneity of the angiogenic response induced in different normal adult tissues by vascular permeability factor/vascular endothelial growth factor. Lab Invest 2000;80:99-115.
75.
Croll SD, Weigand SJ: Vascular growth factors in cerebral ischemia. Mol Neurobiol 1999;155:1915-1927.
76.
Plate KH: Mechanisms of angiogenesis in the brain. J Neuropathol Exp Neurol 1999;58:313-320.
77.
Moro MA, Càrdenas A, Hurtado O, Leza JC, Lizasoain I: Role of nitric oxide after brain ischemia. Cell Calcium 2004;36:265-275.
78.
Danielisova V, Burda J, Nemethova M, Gottlieb M: Aminoguanidine administration ameliorates hippocampal damage after middle cerebral artery occlusion in rat. Neurochem Res 2011;36:476-486.
79.
Johansson BB, Grabowski M: Functional recovery after brain infarction: plasticity and neural transplantation. Brain Pathol 1994;4:85-95.
80.
Zoli M, Grimaldi R, Ferrari R, Zini I, Agnati LF: Short- and long-term changes in striatal neurons and astroglia after transient forebrain ischemia in rats. Stroke 1997;28:1049-1058.
81.
Jablonka JA, Burnat K, Witte OW, Kossut M: Remapping of the somatosensory cortex after a photothrombotic stroke: dynamics of the compensatory reorganization. Neuroscience 2010;165:90-100.
82.
Barde YA, Edgar D, Thoenen H: Purification of a new neurotrophic factor from mammalian brain. EMBO J 1982;1:549-553.
83.
Zoli M, Grimaldi R, Ferrari R, Zini I, Agnati LF: Short-and long-term changes in striatal neurons and astroglia after transient forebrain ischemia in rats. Stroke 1997;28:1049-1058.
84.
Schierling W, Troidl K, Troidl C, Schmitz-Rixen T, Schaper W, Eitenmüller IK: The role of angiogenic growth factors in arteriogenesis. J Vasc Res 2009;46:365-374.
85.
Lin TN, Te J, Lee M, Sun GY, Hsu CY: Induction of basic fibroblast growth factor (bFGF) expression following focal cerebral ischemia. Brain Res Mol 1997;49:255-265.
86.
Tahergorabi Z, Khazaei M: A review on angiogenesis and its assays. Iranian J Basic Med Sci 2012;15:1110-1126.
87.
Ohno M, Cooke JP, Dzau VJ, Gibbons GH: Fluid shear stress induces endothelial transforming growth factor beta-1 transcription and production. Modulation by potassium channel blockade. J Clin Invest 1995;95:1363-1369.
88.
Merrilees MJ, Sodek J: Synthesis of TGF-beta 1 by vascular endothelial cells is correlated with cell spreading. J Vasc Res 1992;29:376-384.
89.
Delavaran H, Sjunnesson H, Arvidsson A, Lindvall O, Norrving B, van Westen D, Kokaia Z, Lindgren A: Proximity of brain infarcts to regions of endogenous neurogenesis and involvement of striatum in ischaemic stroke. Eur J Neurol 2013;20:473-479.
90.
Kokaia Z, Lindvall O: Neurogenesis after ischaemic brain insults. Curr Opin Neurobiol 2003;13:127-132.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.